bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-17. HIGH-GRADE GLIOMA IN VERY YOUNG CHILDREN; A SINGLE-CENTER 11-YEAR-EXPERIENCE
Authors: El-ayadi Moatasem , Shawky Omar , Naguib Eman , Maher Eslam , Abdelaziz Amal , Ahmed Soha , Refaat Amal , von Bueren André O , Taha Hala , El-naggar Shahenda , El-beltagy Mohamed 
Published: December 2020

Abstract

BACKGROUND
Data about high-grade glioma (HGG) in very young children (≤3 years old at diagnosis) is scarce.

METHODS
180 pediatric HGG patients were treated at the Children Cancer Hospital - Egypt (CCHE-57357) between July 2007 and June 2018, with 17 patients aged ≤3 years at diagnosis. Medical records were retrospectively reviewed for clinical, radiological and histopathological data, treatment received and survival outcome.

RESULTS
Median age was 29.2 months (range: 2.4 – 35.8 months; males = 9). Most frequent pathological diagnosis was Glioblastoma, WHO grade-IV (n = 11, 64.7%) and one patient had H3-mutant diffuse midline glioma. All patients underwent surgery (gross-total resection, n = 6, 35.3%; subtotal-resection, n = 5, 29.4%; biopsy, n = 6, 35.3%). One patient (age = 7 months) progressed and died before starting adjuvant therapy. All patients ≤1 year of age (n = 5) received adjuvant chemotherapy (CT) only, older children (n = 11) received adjuvant radiotherapy (RT) (total dose range: 54 – 60 Gy) and CT (CCG-945 protocol). The 1-year overall survival (OS) rate was 47.1%; and event-free survival (EFS) rate was 35.3%. EFS differed between those who received RT and those who did not (1-year EFS 54.5% and 0% respectively, p = 0.001). Compared to older children, anatomical distribution of tumors was significantly different with non-midline locations being the commonest in patients ≤3 years old (88.2% vs 46.4%, p=0.01).

CONCLUSIONS
HGG in very young children arise predominantly in non-midline locations and usually lack the H3-mutation. RT seems crucial in the management of pHGG regardless of age subgroup.
HGG-40. EXCEPTIONAL SYNCHRONOUS OCCURENCE OF A BRAF V600E MUTANT GLIOBLASTOMA AND A H3.3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA: A CASE REPORT
Authors: De Carli Emilie , Boisselier Blandine , Fournier Luc Le , Supiot Stéphane , Mallebranche Coralie , Proust-Houdemont Stéphanie , Duplan Mylène , Pellier Isabelle , Rousseau Audrey 
Published: December 2020

Abstract
We report herein the case of a 17-year-old female who presented with intracranial hypertension and diplopia. Magnetic resonance imaging showed a large left cystic and solid temporoparietal lesion, associated with an infiltrating lesion of the brainstem, hypointense in T1 and hyperintense in FLAIR sequences, without enhancement after injection of gadolinium. Complete resection of the parietal mass and biopsy of the brainstem lesion were performed. Histopathological analysis of the parietal mass showed glioblastoma (WHO grade IV) with no IDH1/2 or H3.3/H3.1 gene mutation detected by Sanger sequencing. Immunohistochemistry found the expression of the proteins of mismatch repair system. Whole exome and RNA sequencing identified a BRAF-V600E mutation. The brainstem lesion was a diffuse midline glioma, H3K27M-mutant (grade IV) according to the 2016 WHO classification. Pan-genomic SNP arrays of the 2 tumors showed distinct genetic alterations. The parietal glioblastoma displayed complex genomic alterations whereas the brainstem glioma harbored chromosome 7q gain, chromosome 9p and 10 losses, and RB, TP53 and CDKN2A homozygous deletions. The patient was treated by concomitant radiochemotherapy (according to Stupp protocol). After 12 cycles of temozolomide, there was complete remission persistant in the parietal lobe. The brainstem tumor was stable but progressed after 3 months of temozolomide discontinuation. Treatment with mTOR inhibitors was initiated. At 21-month follow-up, the patient remains with few symptoms. No predisposition syndrome was identified in the patient or her family. Concurrent glioblastomas with distinct driver gene mutations are exceptional.
HGG-56. EXTENSIVE MOLECULAR HETEROGENEITY WITHIN H3-/IDH-WILDTYPE PEDIATRIC GLIOBLASTOMA
Authors: Blattner-Johnson Mirjam , Sahm Felix , Sill Martin , Sturm Dominik , Kramm Christof M , Pfister Stefan M , Jones David 
Published: December 2020

Abstract
About half of all pediatric high-grade gliomas (HGG) harbor mutations in histone 3 or IDH genes. The remaining HGG are currently broadly classified as H3-/IDH-wild-type. Since the introduction of a uniform approach to DNA methylation-based classification of CNS tumors in 2018, DNA methylation data from over 45,000 CNS tumor samples have been generated. From this large cohort, a number of smaller yet distinct subgroups start to emerge within H3-/IDH-wild-type HGG. Three such subgroups are enriched for focal gene amplifications and have been provisionally termed pedGBM_MYCN, pedGBM_RTK1 and pedGBM_RTK2. Since a significant subset of samples in each subgroup is lacking characteristic alterations, we further investigated the molecular and transcriptional composition of H3-/IDH-wild-type HGG. We evaluated DNA methylation and copy-number profiles in &gt;1000 tumors classified as H3-/IDH-wild-type HGG. Tumors classified pedGBM_MYCN showed a focal MYCN amplification in 25%, with a similar fraction showing amplification of EGFR (8% of samples harbored both alterations) compared to 4% and 4% in pedGBM_RTK1 and 14% and 22% in pedGBM_RTK2. Deletion of CDKN2A/B was much more prevalent in the pedGBM_RTK2 subgroup (~50% compared to 27% in pedGBM_RTK1 and &lt;10% in the pedGBM_MYCN group). We defined a pedGBM_MYCN transcriptional signature, which will be helpful in identifying subgroup-defining mechanisms and alterations. Initial results suggest an involvement of the sonic hedgehog pathway and genes controlling stem-cell pluripotency. Patient-derived xenograft models and murine neural stem cells are now being used for functional characterization and pre-clinical testing of potential drug targets in these molecularly defined subgroups.
IMMU-08. reMATCH PROTOCOL: PHASE II STUDY OF EX-VIVO EXPANDED AUTOLOGOUS TUMOR SPECIFIC LYMPHOCYTE TRANSFER (X-ALT) + TOTAL TUMOR RNA DC VACCINE (TT-RNA DC) DURING RECOVERY FROM MYELOABLATIVE CHEMOTHERAPY (MAC) AND PERIPHERAL BLOOD STEM CELL (PBSC) RESCUE OR NON-MYELOABLATIVE CHEMOTHERAPY (NMAC) AND PBSC IN PATIENTS (PTS) WITH RECURRENT PNET (R-PNET)
Authors: Gururangan Sridharan , Hwang Eugene , Dhall Girish , Yegorov Oleg , Governale Lance , Blatt Jason , Horn Biljana , Mitchell Duane 
Published: December 2020

Abstract
A phase II study was performed to assess vaccine-related toxicities and efficacy of x-ALT+tt-RNA DC following MAC +PBSC (group A) or NMAC +PBSC (group B) in pts with r-PNET. METHODS: Eligible pts underwent biopsy to confirm r-PNET and obtain tumor for vaccine preparation. Pts with local (group A) or metastatic (group B) disease received cytoreductive induction chemotherapy prior to either MAC (carboplatin+ thiotepa+ etoposide) or NMAC (cyclophosphamide + fludarabine) respectively and then received one dose of x-ALT (3 x 107cells/kg), PBSC, and 3 doses of bi-weekly intradermal tt-RNA DCs (107cells each). Patients were followed for survival and vaccine-related toxicities. Correlative studies included TCR RNA sequencing and measurement of serum cytokines. RESULTS: 20 evaluable pts (75% males) [Medulloblastoma 17, PNET 3; unifocal 40%] were treated on protocol (group A 7, group B 13). There were no significant vaccine-related toxicities. At a median follow-up of 8.5 months, 5 patients (all with medulloblastoma) are alive following vaccine therapy; 2 pts with SD (3.5+ and 6.5+ months) and 3 pts with PD that stabilized with salvage therapies (26+, 31+, and 46+ months respectively). One patient with medulloblastoma and bone marrow involvement who had PD despite MAC, had an almost complete response one month following x-ALT + tt-RNA DCs and TCR RNA sequencing demonstrated massive clonal expansion of T cells. Correlative studies are ongoing. CONCLUSIONS: x-ALT+tt-RNA DC following either MAC or NMAC is safe and shows signs of biologic and possible clinical activity in some pts with r-PNET.
IMMU-10. INTERIM ANALYSIS OF THE HIT-HGG REZ IMMUNVAC STUDY - DENDRITIC CELL VACCINATION WITH PARTIAL TREG DEPLETION IN CHILDREN, ADOLESCENTS, AND ADULTS WITH RELAPSED HIGH-GRADE GLIOMAS
Authors: Eyrich Matthias , Krauss Jürgen , Rachor Johannes , Monoranu Camelia , Bison Brigitte , Löhr Mario , Rückriegel Stefan , Wölfl Matthias , Miller Elisabeth , Schlegel Paul G , Kramm Christof 
Published: December 2020

Abstract
Efficacy of therapeutic dendritic cell vaccines (DCV) can be limited by immunosuppressive mechanisms in the micromilieu of high-grade gliomas. In the HIT-HGG-Rez Immunovac trial (Eudra-CT 2013-000419-26), we investigate whether a reduction of Treg with metronomic cyclophosphamide (metrCyc) might be a feasible option to improve vaccine efficacy. 10 pediatric (mean age 11.4±4.2y) and 5 adult patients (mean age 39.5±19.9y) with relapsed glioblastoma were treated according to the HIT-HGG-Rez Immunovac protocol so far. 2 children were treated within the trial, the other 13 in the pilot phase. Patients received upfront oral metrCyc for 2–4 weeks. After reoperation and monocyte-apheresis, patients received 4 weekly intradermal doses of autologous, TNFa/IL-1ß matured DCs pulsed with tumor lysate in imiquimod-prepared skin. Thereafter, tumor lysate boosts were given. All patients received at least 5 vaccines (4xDCs, 1xlysate boosts). MetrCyc was well tolerated and led to a reduction in Treg-frequency of 35.6±17.8% followed by a rebound after cessation of metrCyc. Importantly, 13/14 analyzed patients showed a positive IFNg-T-cell response against autologous tumor lysate with a tendency to decrease over time. 6-month overall survival was 100%, compared to 65% in a historical control. Mean PFS and OS were 5.7 and 21.1 months with no difference between adults and children. We conclude that DCV in combination with partial Treg depletion is feasible, safe, and related with a high rate of tumor-specific IFNg-responses. As the clinically and immunologically beneficial effects seem to diminish over time, we aim to combine our approach with checkpoint inhibition in the next amendment.
IMMU-21. INVESTIGATION OF WHITE BLOOD CELL CHARACTERISTICS IN CSF SAMPLES AT PEDIATRIC BRAIN TUMOR DIAGNOSIS
Authors: Greer Hunter , Campbell Kristen , Samay Sadaf , Green Adam 
Published: December 2020

Abstract

BACKGROUND
There has been a recent surge in investigation of immunity and immunotherapy, but their role in pediatric brain tumors is incompletely defined. We hypothesized that investigating an understudied dataset, WBC and differential results in CSF drawn at the time of pediatric brain tumor diagnosis to look for microscopic metastases, would provide insight into the role of immunology and potential for immunotherapy in these diseases and correlate with prognosis and/or metastasis.

METHODS
We conducted a retrospective comparison analysis of CSF values in 349 patients at our institution from samples drawn within 60 days of initial CNS tumor diagnosis from 1998–2018. We examined total nucleated cell count, absolute counts and percentages for WBC subtypes. We compared CSF values by tumor cell presence, patient vital status, and disease group: atypical teratoid rhabdoid tumor, ependymoma, germinoma, high-grade glioma (HGG), low-grade glioma (LGG), medulloblastoma, non-germinomatous germ cell tumor, and other embryonal tumors (OET). We used Wilcoxon and Kruskal-Wallis tests for comparisons.

RESULTS
Overall, higher lymphocyte percentage (p=0.002) and lower monocyte percentage (p=0.007) were associated with survival. WBC characteristics did not differ significantly based on tumor cell presence. Compared to medulloblastoma, ependymoma showed a more active CSF immune response, while LGG, HGG, and OET showed a less active response, based on total WBC and/or absolute neutrophil count (p=0.001–0.007).

CONCLUSIONS
Higher lymphocyte and lower monocyte percentages in CSF correlated with better prognosis overall; causality requires further investigation. Tumor subtypes varied in their immune stimulation, offering potential insight into which will be amenable to immunotherapy.
LGG-05. MOLECULAR GUIDED THERAPY FOR A PEDIATRIC LOW GRADE GLIOMA: A CASE REPORT
Authors: VonBergen Jayne , Armstrong Beth , Schmitt Morgan 
Published: December 2020

Abstract
Low grade gliomas are the most common type of central nervous system tumors among children. Despite the fact that they are not typically life threatening, low grade gliomas remain a significant clinical challenge. Case Study: Patient is a 4-year-old male who presented at 20 months of age with several weeks of ataxia, emesis, and head tilt. Imaging revealed a right temporal lobe lesion; he was subsequently taken to surgery, where a gross total resection was achieved. Imaging 9 months post resection revealed recurrent disease within the right temporal region with leptomeningeal involvement. Four months later imaging revealed progression of multifocal disease and new growth within the sella. At this time the patient started standard treatment, Carboplatin and Vincristine, per CCG 9952A. Persistent slow progression was observed despite receiving standard therapy. The patient developed a grade 3 reaction to carboplatin, worsening with each subsequent dose. At this time, he was referred to our Precision Genomics Neuro Oncology program for tumor molecular characterization. Somatic tumor testing revealed an ETV6-NTRK3 fusion, at which time standard treatment was stopped, and patient began targeted therapy, Larotrectinib. Imaging was preformed 2 months post start of targeted therapy and revealed interval decrease in size of previously enhancing nodular lesions; findings consistent with treatment response. Disease burden continues to decrease with therapy. This case illustrates a clear benefit of using molecular guided therapy in low grade gliomas.
LGG-13. THE CLINICAL AND MOLECULAR LANDSCAPE OF GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS
Authors: Bennett Julie , Fang Karen , Sheth Javal , Ryall Scott , Martin Komosa , Nunes Nuno , Nobre Liana , Perry James , Sahgal Arjun , Mason Warren , Das Sunit , Gao Andrew , Tsang Derek , Nguyen Lananh , Laperriere Normand , Keith Julia , Munoz David , Tabori Uri , Hawkins Cynthia 
Published: December 2020

Abstract

OBJECTIVE
Pediatric low grade gliomas are typically driven by MAPK upregulation with excellent long-term survival. In contrast, adult lower grade gliomas commonly harbor IDH-1 mutations and undergo malignant transformation. Gliomas in adolescents and young adults (AYA) are an orphan group of tumors that have been poorly described. We aim to determine the clinical and molecular landscape of AYA gliomas.

METHODS
A multi-institutional population based cohort of 839 patients diagnosed with glioma between 15–40 years has been identified. Complete molecular analysis, long term outcome and therapeutic data are being collected.

RESULTS
Of 364 AYA gliomas analyzed, the prevalence of WHO grade I tumors was highest in those &lt;21 years (54%), while the prevalence of higher grade tumors increased with age. Interestingly, only 38% harbor IDH-1 mutations while 23% harbor pediatric mutations, including 8% with BRAF p.V600E, and 4% with KIAA1549:BRAF fusion. The median age for IDH-1 mutation is 32 years, with highest frequency in WHO grade II and III tumors. In contrast, BRAF alterations were most frequently observed in WHO grade I and II tumors and enriched in those less than 20 years. Five-year progression-free survival for BRAF fusion, p.V600E and IDH-1 p.R132H were 81%, 78% and 26% respectively. No survivors were observed in H3 p.K27M and p.G34R gliomas (p&lt;0.0001).

CONCLUSIONS
Gliomas in AYA overlap pediatric and adult classification and exhibit enrichment for pediatric alterations. As the latter are associated with improved PFS and are amenable to targeted therapies, this should be considered in the work up of these tumors.
LGG-17. SYNERGISTIC ACTIVITY OF MAPK INHIBITOR CLASSES REVEALED BY A NOVEL CELL-BASED MAPK ACTIVITY PEDIATRIC LOW-GRADE GLIOMA ASSAY
Authors: Usta Diren , Sigaud Romain , Buhl Juliane L , Selt Florian , Marquardt Viktoria , Pauck David , Pusch Stefan , Ecker Jonas , Hielscher Thomas , Vollmer Johanna , Sommerkamp Alexander C , Rubner Tobias , Hargrave Darren , van Tilburg Cornelis M , Pfister Stefan M , Jones David T W , Remke Marc , Brummer Tilman , Witt Olaf , Milde Till 
Published: December 2020

Abstract
Pilocytic astrocytomas (PAs) and other pediatric low-grade gliomas (pLGGs) exhibit aberrant activation of the MAPK signaling pathway caused by genetic alterations, most commonly KIAA1549:BRAF fusions, BRAF V600E and NF1 mutations. In such a single-pathway disease, novel drugs targeting the MAPK pathway (MAPKi) are prime candidates for treatment. We developed an assay suitable for pre-clinical testing of MAPKi in pLGGs, aiming at the identification of novel MAPK pathway suppressing synergistic drug combinations. We generated a reporter plasmid (pDIPZ) expressing destabilized firefly luciferase driven by a MAPK-responsive ELK-1-binding element, packaged in a lentiviral vector system. We stably transfected pediatric glioma cell lines with a BRAF fusion (DKFZ-BT66) and a BRAFV600E mutation (BT-40) background, respectively. Measurement of MAPK pathway activity was performed using the luciferase reporter. pERK protein levels were detected for validation. We performed a screen of a MAPKi library and calculated Combination Indices of selected combinations. The MAPKi library screen revealed MEK inhibitors as the class inhibiting the pathway with the lowest IC50s, followed by ERK and second generation RAF inhibitors. Synergistic effects in both BRAF-fusion and BRAFV600E mutation backgrounds were observed following combination treatments with different MAPKi classes (RAFi/MEKi, &gt; RAFi/ERKi &gt; MEKi/ERKi). We have generated a novel reporter assay for medium- to high-throughput pre-clinical drug testing of MAPKi in pLGG cell lines. MEK, ERK and next-generation RAF inhibitors were confirmed as potential treatment approaches for KIAA1549:BRAF and BRAFV600E mutated pLGGs. Synergistic suppression of MAPK pathway activity upon combination treatments was revealed using our assay in addition.
LGG-23. EXCELLENT CLINICAL / RADIOLOGICAL RESPONSE TO BRAF INHIBITION IN A YOUNG CHILD WITH IN-OPERABLE SUPRA-SELLAR PILOCYTIC ASTROCYTOMA
Authors: Chapman Stacy , Serletis Demitre , Kazina Colin , Rafay Mubeen , Krawitz Sherry , Rozovsky Katya , Vanan Magimairajan Issai 
Published: December 2020

Abstract
In-operable low grade gliomas (LGG) in the pediatric population continue to present a treatment dilemma. Due to the low-grade nature of these tumors, and variable response to chemotherapy / radiation, the choice of adjuvant treatment is difficult. Overall survival is directly related to the degree of surgical resection, adding complexity to these inoperable tumors. Current chemotherapeutic regimen for these inoperable tumors includes vincristine (VCR) and carboplatin (Carbo). With advancements in the molecular characterization of gliomas, the role of targeted therapy has come into question. We present a 2-year-old female with biopsy proven Pilocytic Astrocytoma (positive BRAF-V600E mutation) involving the hypothalamic/optic chiasm region. She presented with ataxic gait, bi-temporal hemianopia, obstructive hydrocephalus and central hypothyroidism, which progressed to altered consciousness, and right hemiparesis due to location/mass effect of the tumor. She was initially treated with chemotherapy (VCR/Carbo) but her tumor progressed at 6 weeks of treatment. As her tumor was positive for BRAF-V600E mutation, she was started on Dabrafenib monotherapy, resulting in dramatic improvement in her clinical symptoms (able to stand, improved vision), and a 60% reduction in tumor size at 3-months. At 6-months, follow up MRI showed slight increase in the solid portion of the tumor, with no clinical symptoms. We plan to add MEK inhibitor (Trametinib) and continue with Dabrafenib. Our experience and literature review suggests that LGG with BRAF-V600E mutations may benefit from upfront targeted therapy. Prospective clinical trials comparing the efficacy of BRAF inhibitors versus standard chemotherapy in LGG with BRAF mutations are urgently needed.
LGG-25. A PHASE 2 STUDY OF TRAMETINIB FOR PATIENTS WITH PEDIATRIC GLIOMA WITH ACTIVATION OF THE MAPK/ERK PATHWAY. TRAM-01
Authors: Perreault Sébastien , Larouche Valérie , Tabori Uri , Hawkins Cynthia , Lippé Sarah , Ellezam Benjamin , Décarie Jean-Claude , Théoret Yves , Métras Marie-Élaine , Sultan Serge , Cantin Édith , Routhier Marie-Ève , Caru Maxime , Legault Geneviève , Bouffet Eric , Lafay-Cousin Lucie , Hukin Juliette , Erker Craig , Jabado Nada 
Published: December 2020

Abstract

BACKGROUND
Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. We hypothesize that we will observe responses in recurrent/refractory PLGG treated with trametinib.

METHODS
This is a multicenter phase II including three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). Patients will receive daily oral trametinib for a total of 18 cycles of 28 days. A total of 104 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment.

RESULTS
As of January 7 2020, 28 patients have been enrolled (NF1: 6 patients, KIAA1549-BRAF fusion: 17, other: 5 including 3 patients FGFR1 alteration). Median age is 8.5 years (range 2.5–25.4 years). Median follow-up is currently 4.6 months (range 0.16–14.7 months). Twenty patients are currently evaluable. Best response includes: 1 complete response (5%), 3 partial response (15%), 4 minor response (20%), 8 stable disease (40%), 4 progressive disease (20%). 8 patients (28,5%) discontinued treatment: 4 for progressive disease, 3 adverse event (alanine aminotransferase increase), 1 withdrew.

CONCLUSION
Trametinib is potential effective targeted therapy for patients with recurrent/refractory PLGG. Overall treatment is well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.