bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMG-01. DWI RATIO OF HISTOLOGICAL MOLECULAR SUBTYPES OF PAEDIATRIC MEDULLOBLASTOMAS
Authors: Tang Phua Hwee , Low Sharon , Tan Enrica , Chang Kenneth 
Published: December 2020

Abstract

AIM
To evaluate if diffusion weighted imaging (DWI) ratio on MRI is able to distinguish between the histological molecular subtypes of paediatric medulloblastomas.

MATERIALS AND METHODS
From 2002 to 2017, 38 cases of medulloblastoma with preoperative MRI available had histological subtyping performed with NanoString nCounter technology. The medulloblastomas were classified into 4 subtypes. There were 3 Sonic Hedgehog (SHH), 9 Wingless (WNT), 12 Group 3 and 14 Group 4 subtypes. Single operator manually outlined solid non-haemorrhagic component of the tumour on DWI images with largest axial tumour cross sectional diameter, correlating with the other MRI images (T1 pre and post contrast, SWI/GRE, FLAIR) to identify areas of haemorrhage. The same operator also drew region of interest to identify normal cerebellar tissue on the same axial images on which the tumour was outlined. All MRI images were obtained from the department’s Radiological Information System Picture Archiving and Communicating System (RIS PACS). DWI ratio for each case was obtained by dividing the values obtained from tumour by normal cerebellar tissue seen on the same axial image.

RESULTS
DWI ratio of all medullloblastomas is 1.34 +/- 0.18. DWI ratio of SHH subtype is 1.43 +/- 0.07. DWI ratio of WNT subtype is 1.40 +/- 0.07. DWI ratio of Group 3 subtype is 1.31 +/- 0.25. DWI ratio of Group 4 subtype is 1.30 +/- 0.17. There is no significant statistical differences in the DWI ratio between the various subtypes.

CONCLUSION
DWI ratio of medulloblastoma is unable to distinguish between the 4 medulloblastoma subtypes.
IMG-02. USEFUL DIAGNOSIS OF PEDIATRIC CYSTIC BRAIN TUMORS USING MULTIPLE POSITRON EMISSION TOMOGRAPHY STUDIES
Authors: Miyake Keisuke , Fujimori Takeshi , Toyota Yasunori , Ogawa Daisuke , Hatakeyama Tetsuhiro , Okauchi Masanobu , Kawanishi Masahiko , Tamiya Takashi 
Published: December 2020

Abstract

OBJECTIVE
Pediatric brain tumors are primarily diagnosed using MRI or CT examination; however, determining the correct diagnosis using only morphological MRI can sometimes be challenging. Positron emission tomography (PET) uses radiotracers for metabolic and molecular imaging. We examined the accumulation of multiple PET (FDG, MET, FLT, and FMISO) studies for diagnosing pediatric cystic brain tumors.

METHODS
We performed PET scans for eight pediatric patients (five pilocytic astrocytoma, one pleomorphic xanthoastrocytoma, one diffuse astrocytoma with IDH1 mutation, one ganglioglioma) from April 2010 to December 2019. The resulting studies were compared by measuring the tumor-to-normal lesion (T/N) ratio of FDG, MET, and FLT and the tumor-to-blood value (T/B) ratio of FMISO between each pediatric cystic brain tumor.

RESULTS
All pediatric brain tumors showed tumor uptake of FDG, MET, and FLT. We could not examine FMISO PET for one diffuse astrocytoma with IDH1 mutation. The T/N ratios of FDG, MET, and FLT and the T/B ratio of FMISO were 1.07, 2.76, 4.6, and 1.12 for pilocytic astrocytoma; 0.65, 4.6, 7.67, and 1.38 for pleomorphic xanthoastrocytoma; 0.61, 2.14, and 3.82 for diffuse astrocytoma with IDH1 mutation; and 0.79, 1.78, 5, and 1.49 for ganglioglioma, respectively. The T/N ratios of MET and FLT for pleomorphic xanthoastrocytoma were high, but the Ki-67 labeling index was 1%. In the ganglioglioma, the T/N ratio of FLT was high, but the T/N ratio of MET was low.

CONCLUSION
Specialized multiple PET accumulation patterns for tumors are useful for discriminating each tumor.
IMG-09. RESPONSE ASSESSMENT IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): RECOMMENDATIONS FROM THE RESPONSE ASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY COMMITTEE
Authors: Cooney Tabitha , Cohen Kenneth J , Guimaraes Carolina V , Dhall Girish , Leach James , Massimino Maura , Erbetta Alessandra , Chiapparini Luisa , Malbari Fatema , Kramer Kim , Pollack Ian F , Baxter Patricia , Laughlin Suzanne , Patay Zoltan , Poussaint Tina Young , Warren Katherine E 
Published: December 2020

Abstract
Optimizing the conduct of clinical trials for diffuse intrinsic pontine glioma (DIPG) involves use of consistent, objective disease assessments and standardized response criteria. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, an international panel of pediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address unique challenges in assessing response in children with CNS tumors. A subcommittee of RAPNO was formed to specifically address response assessment in children and young adults with DIPG and to develop a consensus on recommendations for response assessment. Distinct issues related to the response assessment of DIPG include its definition and recent molecular classifications, dearth of imaging response data, the phenomena of pseudoprogression, and measuring response in the era of focal drug delivery. The committee has recommended response be assessed using magnetic resonance imaging (MRI) of brain and spine, neurologic examination, and use of supportive medication, i.e. steroids and anti-angiogenic agents. Clinical imaging standards and imaging quality control are defined. Unique recommendations for DIPG response include an eight-week response duration, a twenty-five percent decrease for partial response, and the distinction of pontine and extra-pontine response for trials that use focal drug delivery. The recommendations presented here represent an initial effort to uniformly collect and evaluate response assessment criteria; these recommendations can now be incorporated into clinical trials to assess feasibility and corroboration with patient outcomes.
IMG-12. CHARACTERISATION OF MODELS OF H3F3A_G34R/V MUTANT PAEDIATRIC GLIOBLASTOMA IN VIVO USING MAGNETIC RESONANCE IMAGING
Authors: Boult Jessica , Bjerke Lynn , Fofana Mariama , Vinci Maria , Molinari Valeria , Mackay Alan , Temelso Sara , Box Gary , Eccles Suzanne , Carcaboso Angel , Castro Maria , Waanders Angela , Cole Kristina , Jones Chris , Robinson Simon 
Published: December 2020

Abstract
Approximately 15% of paediatric/young adult cerebral hemispheric glioblastomas (pGBM) harbour G34R/V mutations in H3F3A, encoding the histone H3.3 variant. Development of novel therapeutic interventions demands models that accurately recapitulate this subset of disease and sensitive imaging methods with which to study tumours in situ. Three H3F3A_G34R primary-patient-derived cultures, alongside established cell-line KNS42 (H3F3A_G34V), were implanted orthotopically in immunocompromised mice. KNS42 (TP53_R342*) tumours were clearly detectable using T2-weighted (T2w)-MRI, enhanced following contrast agent administration, indicating impaired blood-brain barrier (BBB) integrity, and demonstrated minimal invasion. OPBG_GBM_001 cells (TP53_89-90X,ATRX_II2133-2144X) formed infiltrative tumours that were hyperintense on T2w-MRI and demonstrated contrast-enhancement suggestive of heterogeneous BBB integrity. HSJD_GBM_002 cells (TP53_P278T,ATRX_R666*) spread diffusely throughout the brain with their full extent typically not discernible by T2w-MRI, the BBB also remaining intact. No evidence of CHOP_GBM_001 tumour was detected by MRI 11months post-implantation. Immunocompetent syngeneic models using tumour cells induced by mutations modelling hemispheric pGBM (NRAS/shP53/shATRX±H3.3G34R) are being explored. Fast growing heterogeneous lesions with variable contrast-enhancement were identified; the H3.3G34R mutation conferred longer median survival (2 clones:25/28days, control:14days). These models have the advantage of an intact immune system and short latency for initial efficacy studies. Primary pGBM cells yield tumours that are more representative of the spectrum of clinical disease; variable hyperintensity on T2w-MRI corresponding to cellular density, with diffusely infiltrative disease less clearly definable, a paucity of oedema and a range of contrast-enhancement. Pathological features including giant multinucleated cells, and mitotic figures were also evident.
IMG-21. PROSPECTIVE PREOPERATIVE DETERMINATION OF ISOCITRATE DEHYDROGENASE MUTATION IN GLIOMAS USING SPECTRAL EDITING MAGNETIC RESONANCE SPECTROSCOPY
Authors: Nguyen Thanh , Melkus Gerd , Taccone Michael , Ghinda Diana , Torres Carlos , Zakhari Nader , Woulfe John , Jansen Gerrard , Cameron Ian , Moldovan Ioana , Alkherayf Fahad 
Published: December 2020

Abstract

BACKGROUND
Gliomas are the most common malignant brain tumors in children and adults. A subset of these tumors harbour mutations in the enzyme isocitrate dehydrogenase (IDH) which produces the novel oncometabolite 2-hydroxyglutarate (2HG). In general, patients with an IDH mutant glioma have a longer survival—often necessitating more re-treatment sessions over the span of a patient’s life and surveillance monitoring for tumor recurrence. The need to non-invasively detect early evidence of tumor recurrence is therefore heightened in this unique subset of patients with extended survival. As magnetic resonance spectroscopy (MRS) has been demonstrated to measure biochemical components of intracranial tumors using MRI, we conducted a study in 58 pre-operative adult patients to determine if a diagnosis of IDH mutant glioma could be made confidently using imaging data.

METHODS
Patients underwent neuroimaging for diagnosis or preoperative planning on a 3 tesla MR scanner. A MEGA-PRESS spectral editing technique was employed. Imaging findings were directly compared to post-operative histopathologic diagnosis. RESUTLS: For all patients with gliomas from grade II to IV, detection of 2-HG with MEGA-PRESS sequence had a sensitivity between 48% and 81%, specificity between 60% and 100%, PPV between 53% and 100% and NPV between 77% and 85% depending on the CRLB threshold. Among the different metabolite ratios, a 2-HG/NAA ratio &gt;0.034 had the highest sensitivity and specificity, 86% and 73% respectively.

DISCUSSION
Magnetic resonance spectroscopy (MRS) is an underused advanced MR technique that deserves consideration in pediatric neuro-oncology given its utility in non-invasively detecting malignant gliomas.
IMMU-03. UPDATES ON BRAINCHILD-01, -02, AND -03: PHASE 1 LOCOREGIONAL CAR T CELL TRIALS TARGETING HER2, EGFR, AND B7-H3 FOR CHILDREN WITH RECURRENT CNS TUMORS AND DIPG
Authors: Vitanza Nicholas , Gust Juliane , Wilson Ashley , Huang Wenjun , Perez Francisco , Wright Jason , Leary Sarah , Cole Bonnie , Albert Catherine , Pinto Navin , Orentas Rimas , Jensen Michael , Park Julie 
Published: December 2020

Abstract
We report preliminary results of three Phase 1 trials of repetitively dosed locoregional CAR T cells for children with recurrent/refractory CNS tumors, targeting HER2 (BrainChild-01), EGFR (BrainChild-02), and B7-H3 (BrainChild-03). Cells are delivered into the tumor cavity (Arm A) or ventricular system (Arm B and BrainChild-03’s DIPG-specific Arm C). Primary endpoints are feasibility and safety. Successful CAR T cell manufacture occurred in 2/2 subjects (BrainChild-01) and 2/3 (BrainChild-02). All subjects tolerated intra-patient dose escalation from 1x107 to 2.5x107 cells/dose without DLTs. Two subjects were evaluable on BrainChild-01 (S-001: glioblastoma, Arm A, survival 173 days post-first infusion, received 6 infusions; S-002: ependymoma, Arm B, survival 111 days, 9 infusions). One subject was evaluable on BrainChild-02 (glioblastoma, Arm A, withdrew from trial at 49 days, 5 infusions). One enrolled patient on BrainChild-03 has not begun treatment. None of the subjects developed new neurologic toxicities, although transient worsening of baseline tumor-related signs and symptoms were seen. Secondary endpoints are efficacy and disease response. No objective radiographic responses have been observed. Both BrainChild-01 subjects had transient systemic CRP elevations following infusions (S-001: peak of 3.9 post Course 1 Week 1; S-002: peak of 2.3 post Course 2 Week 1), possibly indicating an inflammatory response. Both subjects had post-infusion CSF cytokine elevations (CXCL10, GCSF, GM-CSF, IFNa2, IFNg, IL-10, IL12-p40, IL12-p70, IL-15, IL-1a, IL-3, IL-6, IL-7, TNFa, VEGF) without concurrent systemic changes. In summary, we provide preliminary evidence of safety and feasibility of intracranial delivery of CAR T cells for pediatric CNS tumors.
IMMU-17. CAR T CELLS TARGETING THE INTEGRIN ALPHAVBETA3 EXHIBIT ROBUST ANTI-TUMOR RESPONSES AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND GLIOBLASTOMA (GBM)
Authors: Cobb Dustin , de Rossi Jacopo , Liu Lixia , An Erin , Lee Daniel 
Published: December 2020

Abstract
Effective therapies for DIPG and GBM are lacking. CD19 chimeric antigen receptor (CAR) T cells are highly effective in patients with refractory B-cell malignancies. We aim to develop novel CARs for high-grade gliomas. The integrin complex alphavbeta3 was selected as a CAR-T cell target due to its expression on gliomas and their vasculature, yet with minimal expression throughout normal tissues, vessels and organs. Indeed, a majority of DIPG and GBM cell lines express surface α vβ 3. Second-generation CAR-T cells expressing an anti-α vβ 3 scFv and either a CD28 or 4-1BB co-stimulatory domain and CD3zeta were constructed. Transduced healthy, donor-derived T cells exhibited high level CAR expression, efficient expansion, and representative populations of memory subsets including central, effector, and stem cell-like memory CAR-T cells. α vβ 3.28z and α vβ 3.BBz CAR-T cells exhibited antigen-specific in vitro cytotoxicity and cytokine production against DIPG and GBM cell lines. Both CARs mediated rapid and robust anti-tumor responses in NSG mice bearing orthotopic DIPG or GBM tumors. 5/13 α vβ 3.28z and 0/14 α vβ 3.BBz treated animals died without detectable disease within 2 weeks of infusion suggesting different toxicity profiles and is consistent with faster CAR-T cell expansion in CD28-versus 4-1BB-containing CD19 CAR-T cells seen clinically. Our results demonstrate that α vβ 3.BBz CAR-T cell therapy may be both highly effective and safe in DIPG and GBM patients. Due to the restricted nature of α vβ 3 expression in normal tissues, the robust responses seen in tumor-bearing mice, and the slower kinetics of α vβ 3.BBz CAR-T cell expansion, a first-in-human clinical trial is being planned.
LGG-04. A PHASE II RE-TREATMENT STUDY OF SELUMETINIB FOR RECURRENT OR PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA (pLGG): A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY
Authors: Fangusaro Jason , Onar-Thomas Arzu , Wu Shengjie , Poussaint Tina Young , Packer Roger , Kilburn Lindsay , Qaddoumi Ibrahim , Dhall Girish , Pollack Ian F , Lenzen Alicia , Partap Sonia , Fouladi Maryam , Dunkel Ira 
Published: December 2020

Abstract
The PBTC conducted a re-treatment study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/progressive pLGG. Eligible patients must have previously enrolled on PBTC-029 or PBTC-029B and progressed after coming off treatment with selumetinib. Patients must have maintained stable disease (SD) for ≥12 courses or had a sustained radiographic response (partial or complete) during their first exposure to selumetinib. Thirty-five eligible patients (median age: 13.11 years [range 7.96–25.33]) were enrolled, 57% of whom had optic pathway or hypothalamic target lesions. At the time of submission, median duration of treatment was 18 courses (range 2–48) and 21 subjects remained on therapy. Best responses reported to date are 6/35 (17%) partial response, 22/35 (63%) SD and 7/35 (20%) progressive disease with a 2-year progression-free survival of 75.7 + 8.3%, which met the design parameters for success. The most common attributable toxicities were grade 1 diarrhea, elevated AST, hypoalbuminemia, elevated CPK, maculo-papular rash, fatigue, paronychia, ALT elevation, acneiform rash and grade 2 CPK elevation. Rare grade 3 toxicities included CPK elevation (3), lymphopenia (2), paronychia (2) and ALT elevation (2). There was only one grade 4 CPK elevation. Five patients (14%) required dose reductions due to toxicity. There does not appear to be a notable difference in toxicities observed during initial selumetinib therapy versus re-treatment. In pLGG that has recurred/progressed following treatment with selumetinib, re-treatment with selumetinib appears to be effective with 80% of patients again achieving response or prolonged stable disease. Long-term follow-up is ongoing.
LGG-11. INSTITUTIONAL EXPERIENCE OF BRAF TARGETING THERAPY
Authors: Lola Gino Bardi , Sato Mariko 
Published: December 2020

Abstract

BACKGROUND
The use of BRAF inhibitors is widely accepted in adult oncology as treatment for BRAF mutated cancers. BRAF alterations are frequently found in both pediatric low grade and high-grade gliomas, which has opened a new door to targeted therapies for pediatric gliomas. Targeted therapy drugs are associated with predictable patterns of adverse events. However treating in children may potentiate unique challenges. We present our institutional experience of targeted therapy with a focus on adverse events.

METHODS
We conducted a retrospective chart review of patients treated with BRAF and/or MEK inhibitors between 2015–2019.

RESULTS
There are nine patients treated with either MEK inhibitor(n=) or the combination therapy(n=). The most common diagnosis was Pilocytic astrocytoma. Targeted therapy was chosen as salvage therapy in all patients. The most common side effect was a pruritic erythematous rash, observed in 8 out of 9 patients. Cardiac toxicity (Grade 2, n=1) and GI toxicity (Grade 3, n=1) were found in patients treated with MEK inhibitor. Both cases resulted in cessation of therapy or significant decreased dose respectively. While two patients died due to progression of disease and two other continued to progress, 5 patients have demonstrated stable disease while on therapy.

CONCLUSIONS
Our study revealed the incidence of severe adverse events in two patients with BRAF targeted therapy. Due to the potential life-long use of targeted therapy, it is important to follow guidelines of adverse event monitoring and to develop a prevention and management strategy for severe adverse events.
LGG-24. CARBOPLATIN-INDUCED HEMATURIA IN A PEDIATRIC PATIENT WITH LOW-GRADE GLIOMA AND REVIEW OF LITERATURE
Authors: Hoover Alex , Sato Mariko 
Published: December 2020

Abstract

OBJECTIVE
In this case report, we present a pediatric patient with gross hematuria and hydroureteronephrosis associated with high dose carboplatin. Given the paucity of literature on the subject, we also conduct and present a review of cases. CASE PRESENTATION: A 6-year-old Caucasian female with history of Type 1 neurofibromatosis was undergoing treatment for a low-grade glioma with monthly high dose carboplatin (560 mg/m2). After 8th dose out of 13, the patient developed severe nausea and vomiting and was admitted for dehydration. She was noted to have microscopic hematuria. After 9th dose, the patient again developed severe nausea, vomiting and gross hematuria with clots. She was admitted and treated with IV hydration. Renal ultrasound showed newly developed bilateral hydroureteronephrosis. Coagulation studies were normal. Multiple cultures and viral studies were negative. Hematuria cleared spontaneously after 4 days of aggressive hydration.

RESULTS
Subsequent carboplatin was given with aggressive hydration and minimized nausea/vomiting and no hematuria was observed. Literature review revealed only 4 reported cases of carboplatin-induced hematuria, including only one pediatric case that occurred in a patient with concurrent thrombocytopenia. Carboplatin may exhibit toxicity to the transitional epithelial cells of the urogenital tract causing hemorrhage from the renal pelvis and ureters. If untreated, this may lead to urinary outflow obstruction and subsequent obstructive nephropathy.

CONCLUSION
We present a rare toxicity, gross hematuria caused by high-dose carboplatin treatment. Providers should be aware of this rare toxicity and provide timely hydration and supportive care to prevent development of obstructive kidney injury and/or renal failure.
LGG-26. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) IN CHILDREN: DIFFERENT CLINICAL PRESENTATIONS AND OUTCOMES
Authors: Valiakhmetova Andge , Papusha Ludmila , Yasko Ludmila , Druy Alexander , Karachunsky Alexander , Novichkova Galina , Hwang Eugene I , Packer Roger J 
Published: December 2020

Abstract
Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely rare disease, newly recognized in the 2016 WHO classification of tumors of the CNS. Most DLGNTs are low-grade neuroepithelial tumors with variable elements of neuronal/neurocytic and glial differentiation, have diffuse leptomeningeal enhancement on MRI, and typically harbor KIAA1549-BRAF fusions. Other alterations, such as the BRAF V600E substitution, are less common. Here, we present three cases of DLGNT with different presentations and outcomes. The first patient is a 2yr-old male with KIAA1549-BRAF fusion, and was treated with Carbo/VCR chemotherapy after a biopsy, with resultant ongoing stable disease for 3.5 years. The second patient, an 8yr-old male had the BRAF V600E point mutation and was treated with conventional chemotherapy (VCR/carboplatin). On progression, he received the BRAF inhibitor vemurafenib, achieving a complete response which last 14 month. The third patient, a 27 month old male, harbored a KIAA1549-BRAF fusion and was treated at diagnosis with the MEK inhibitor trametinib. The tumor has been radiographically stable in the context of clinical improvement for 21 months since the treatment initiation, ongoing 24 month. In summary, we present further evidence of MAPK pathway alterations in children with DLGNT. We describe a range of molecular presentations and clinical outcomes, including one patient treated with conventional chemotherapy with further stabilization of disease during 3.5 years and two patients who were successfully treated with targeted therapy.
LGG-28. NOVEL BRAF INTRAGENIC DELETION IN A GLIOMA: A CASE REPORT OF A PEDIATRIC PATIENT
Authors: Flores Valerie Cruz , Sutcliffe Maxine , Geller Thomas , Gomez Ignacio Gonzalez , Smith Stephanie , Stapleton Stacie 
Published: December 2020

Abstract

BACKGROUND
Numerous variant BRAF genetic alterations have been associated with malignancies. BRAF activating fusions/mutations are frequently present in low grade gliomas. BRAF intragenic deletions have been reported in melanoma, but have not previously been reported in gliomas.

OBJECTIVE
To report a BRAF intragenic deletion in a pediatric patient with recurrent low-grade glioma.

RESULTS
A 3-year-old female underwent a complete resection of a posterior fossa pilocytic astrocytoma. She had recurrences at age 4, and then at age 9; pathology was consistent with pilocytic astrocytoma. Microarray analysis on sample from the first recurrence showed one region of loss encompassing 86 Kbp within the BRAF gene. The deletion breakpoints are within intron 1 and 9, resulting in loss of exons 2 through 9, inclusive. This has been previously described melanoma, but appears to be a novel finding in glioma. It is hypothesized that, since the loss retains the kinase and ATP binding pocket domains but deletes the N-terminal conserved region 1 and 2 (CR1, CR2) of the BRAF gene, it is likely functionally similar to the loss and activation resulting from the more usually described KIAA1549 and BRAF gene fusion.

CONCLUSION
This is the first BRAF intragenic deletion involving exons 2–9 reported in a glioma. Although 86kbp is small using whole genome microarray technology, it is large using sequencing strategies, and a targeted sequencing approach to investigate the BRAF gene would not readily identify this deletion. It is speculated that the deletion may be under ascertained in the pediatric population.