bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-27. ANALYSIS OF IMMUNE SIGNATURES IN PEDIATRIC GLIOBLASTOMAS FOR PATIENT STRATIFICATION TO IMMUNOTHERAPY
Authors: Chandramohan Vidyalakshmi , Evangelous Tyler , Lipp Eric S , Hora Bhavna , Bigner Darell D , McLendon Roger E , Ashley David M
Published: December 2020

BACKGROUND

Pediatric glioblastoma (pGBM), despite being relatively rare (incidence rate: 0.5/100,000), are a leading cause of cancer deaths in children with a median overall survival of 9–15 months. In recent years, immunotherapy has emerged as one of the more promising advances in oncology, with impressive response rates reported in several malignancies. Effective application of immunotherapy in brain tumors depends upon a better understanding of the immune cell phenotype and mechanisms of immunosuppression in these tumors. This understanding will allow for the selection of patient population who are most likely to benefit from immunotherapeutic approaches.

MATERIAL AND METHODS

In order to determine the frequency, distribution, and phenotype of tumor-infiltrating immune cells in pGBMs, we undertook an immunohistochemical survey on 19 recurrent pGBMs for CD3, CD8, CD4, CD163, PD-1, PD-L1, and FoxP3; RNA-Seq was also performed on a subset of 9 cases. Distribution of lymphocytes (LYMPHS) was recorded as intratumoral (IT) or perivascular (PV).

RESULTS

The analysis indicates intratumoral CD3+ LYMPHS are commonly <5% of tumor cell mass; however, approximately half (10/19) of these recurrent pGBM have infiltrates that range from 5 to 30% CD3+ LYMPHS. Of these, 4/10 CD3+ tumors exhibit brisk CD8+ infiltrates that are associated with PD-L1+ tumor cells. These tumors with brisk CD3+/CD8+ LYMPHS and PD-L1+ tumor cells were associated with longer survivals. The data were confirmed by RNA-seq analysis.

CONCLUSION

PD-L1+ pGBMs associated with CD3+/CD8+ LYMPH infiltrates deserve further investigation as candidates for immunotherapy.
LGG-01. CLINICAL MANAGEMENT AND GENOMIC PROFILING OF PEDIATRIC LOW-GRADE GLIOMAS IN SAUDI ARABIA
Authors: Mobark Nahla A , Alharbi Musa , Balbaid Ali Abdullah O , Al-Habeeb Lamees , AlMubarak Latifa , Alaljelaify Rasha , AlSaeed Mariam , Almutairi Amal , Alanazi Fatmah A , Bashawri Yara , Ahmad Maqsood , Al-Banyan Ayman , Alotabi Fahad E , Barakeh Duna , AlZahrani Malak , Al-Khalidi Hisham , Ajlan Abdulrazag , Ramkissoon Lori A , Ramkissoon Shakti H , Abedalthagafi Malak
Published: December 2020

Pediatric Low Grade Gliomas (PLGGs) display heterogeneity regarding morphology, genomic drivers and clinical outcomes. The treatment modality dictates the outcome and optimizing patient management can be challenging. In this study, we profiled a targeted panel of cancer-related genes in 37 Saudi Arabian patients with pLGGs to identify genetic abnormalities that can inform prognostic and therapeutic decision-making. We detected genetic alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient. The KIAA1549-BRAF fusion was the most common alteration (21/37 patients) followed by AFAP1-NTRK2 (2/37) and TBLXR-PI3KCA (2/37) fusions that were observed at much lower frequencies. The most frequently mutated) genes were NOTCH1 3 (7/37), ATM (4/37), RAD51C (3/37), RNF43 (3/37), SLX4 (3/37) and NF1 (3/37). BRAF V600E mutations were observed in only 2/37 patients, while H3F3A (K27M) histone mutations were not detected. Interestingly, we identified a GOPC-ROS1 fusion in an 8-year-old patient whose tumor lacked BRAF alterations and histologically classified as low grade glioma. The patient underwent gross total resection (GTR) currently he is disease free. To our knowledge this is the first report of GOPC-ROS1 fusion in PLGG which may represent a genomically-distinct subgroup of pLGGs that could be targeted with oral target therapy crizotinib. Taken together, we reveal the genetic characteristics of pLGG Saudi patients can enhance diagnostics and therapeutic decisions. In addition, we identified a GOPC-ROS1 fusion that may be a biomarker for pLGG. Our study proves the possibility of using genetic profiling to guide optimal treatment strategies for pLGG in Saudi population
LGG-03. INCIDENCE AND OUTCOME OF PEDIATRIC IDH-MUTANT GLIOMA
Authors: Yeo Kee Kiat , Alexandrescu Sanda , Cacciotti Chantel , Krzykwa Emily , Clymer Jessica , Chordas Christine , Zimmerman Mary Ann , Chi Susan , Warren Katherine , Wright Karen
Published: December 2020

INTRODUCTION

The incidence of IDH mutations in pediatric glioma is unclear. Recent publications suggest rates ranging between 0–20%. Therapy poses challenges as it is unclear if the biology and prognosis of pediatric IDH-mutant gliomas are identical to adults.

METHODS

We performed an IRB approved, systematic retrospective search for IDH-mutant gliomas in the Dana-Farber Cancer Institute/Boston Children’s Hospital database between 2009–2018, analyzing incidence, demographics, histology, co-occurring genetic alterations and outcome.

RESULTS

We identified 575 patients with glioma, ages 0–21 years. Of these, 394 underwent biopsy/resection (0–9 years:n=204; 10–21 years:n=190), with 294 genetic testing. Fifteen of 294 tumors (5%) were IDH1-mutant. Among patients 0–9 years and 10–21 years, 1/156 (0.6%) and 14/138 (10%) had IDH1-mutant tumors, respectively. Among patients 10–21 year old, 13/115 low-grade gliomas were IDH1-mutant (11%). High-grade gliomas accounted for the remaining 23, with one IDH1-mutant glioma (4%). Most common co-occurring genetic alterations for diffuse astrocytoma (n=12) were TP53 (n=9) and ATRX (n=2). Three patients with IDH1-mutant oligodendrogliomas had 1p/19q deletion. Eleven IDH1-mutant patients were evaluable for outcomes with median follow-up of five years. Five-year radiation-free, progression-free and overall survival for patients with low-grade histology were 76% and 100%, respectively. One patient with high-grade glioma recurred 1.2 years after upfront chemo-radiation and died soon after recurrence.

CONCLUSION

IDH-mutant gliomas comprise a small proportion of pediatric gliomas. Incidence rate is higher in the second decade of life. Comparative analyses between pediatric IDH-mutant gliomas and adult historical cohorts are currently underway, evaluating outcomes, radiation therapy and frequency of malignant transformation.
LGG-09. CORRELATING GENETIC SIGNATURE OF PILOMYXOID ASTROCYTOMAS AND PILOCYTIC ASTROCYTOMAS WITH QUALITATIVE AND QUANTITATIVE MR IMAGING CHARACTERISTICS
Authors: Fadel Sandra Abi , Omay Zeynep Erson , Darbinyan Armine , Bronen Richard , Fulbright Robert , Mahajan Amit , Aboian Mariam
Published: December 2020

PURPOSE

Pilomyxoid astrocytomas are predominantly located in supra-chiasmatic region and are more clinically aggressive than pilocytic astrocytomas, although recent WHO 2016 classification placed them into the grade I/II category. In our study, we describe imaging correlation of PMA to their genetic signature.

MATERIALS AND METHODS

We identified 12 pediatric patients with pathologically proven PMA, PA, and PA with myxoid features in an IRB approved study. Three of the tumors had whole exome somatic and germline sequencing. Qualitative MRI characteristics of location, size, enhancement, edema, T2 and T1 intensity, and multifocality were assessed.

RESULTS

Among the PMA, 3 cases were found to have KIAA1549-BRAF fusion, 1 case BRAF V600E mutation, and 2 cases had wildtype BRAF. The BRAF wildtype tumors had atypical imaging features with intraventricular extension of tumor, involvement of frontal lobe parenchyma and one tumor demonstrating increase in size and development of enhancement at 5 years. Whole exome sequencing of BRAF wildtype tumors identified somatic truncation mutations in NF1 R1534X and R1513X with wildtype germline NF1 and missense mutations in KMT2C and GLTSCR1. Among PAM, one was BRAF wildtype with mutations i PTCH1 M956V and PTPN1 (A72V) and demonstrated atypical features of intratumoral hemorrhage on presentation. Among PA, one was positive for KIAA1549-BRAF, one was BRAF wildtype.

CONCLUSIONS

BRAF wildtype PMA and PA demonstrate atypical tumor localization and are associated with atypical genetic mutations on whole exome sequencing. On the contrary, presence of KIAA1549-BRAF fusion or BRAF V600E mutation within PMA and PA correlates with classic qualitative imaging characteristics.
LGG-14. MULTI-OMIC ANALYSIS OF MAPK ACTIVATION IN PEDIATRIC PILOCYTIC ASTROCYTOMA
Authors: Sigaud Romain , Selt Florian , Hielscher Thomas , Overbeck Nina , Usta Diren , Remke Marc , Picard Daniel , Pfister Stephan M , Jones David T W , Brummer Tilman , Witt Olaf , Milde Till
Published: December 2020

Pilocytic astrocytomas (PA) are low-grade gliomas (pLGG) and are the most frequent childhood brain tumors. They are characterized by oncogene-induced senescence (OIS) initiated and sustained by senescence-associated secretory phenotype (SASP) factors. OIS and SASP in PA are thought to be driven by aberrations of the mitogen-activated protein kinase (MAPK) pathway (e.g. KIAA1549:BRAF fusion, BRAFV600E mutation, for the most common MAPK alterations occuring in PA), leading to its sustained activation. The MAPK pathway cascade is activated in a sequential manner: 1) ERK activation, which phosphorylates downstream partners in both cytoplasm and nucleus. 2) ERK-mediated induction of immediate early genes encoding transcription factors. 3) Induction of MAPK target genes expression. 4) Activation of downstream pathways. Our aim is to unravel the molecular partners involved at each level of the sustained MAPK pathway activation in pLGG with different genetic backgrounds (KIAA1549:BRAF fusion and BRAFV600E mutation), and leading to the induction of OIS and SASP factors expression. pLGG cell lines DKFZ-BT66 (KIAA1549:BRAF) and BT-40 (BRAFV600E) were treated with the MEK inhibitor trametinib at key time points, and gene expression profile analysis was performed, allowing transcriptome analysis at each step of the MAPK cascade. This will be combined with a whole proteomic and phospho-proteomic analysis. Combination of the transcriptome and proteome data layers will allow the identification of a) downstream targetable partners activated by the MAPK pathway involved in PA senescence, b) new putative targets that might bring benefit in combination with MAPK inhibitors.
LGG-15. PEDIATRIC LOW-GRADE GLIOMAS IN SAUDI ARABIA: RETROSPECTIVE ANALYSIS OF CHILDREN WITH LOW-GRADE GLIOMAS TREATED IN KING FAHAD MEDICAL CITY KFMC- SINGLE INSTITUTIONAL EXPERIENCE
Authors: Alammar Fahad , Alharpi Musa , Ahmad Maqsood , Al-Banyan Ayman , Alotaibi Fahad E , Shakweer Wafa Al , Abedalthagafi Malak , Mobark Nahla Ali
Published: December 2020

Pediatric Low-grade gliomas (PLGGs) are extremely heterogeneous tumors and account for approximately 35% of childhood brain tumors. This retrospective study on 55 newly diagnosed children (<14 ys) with pathologically confirmed LGG from 2006 to 2016 aimed to review demographic data, clinical and therapeutic aspects and treatment outcome of PLGGs in children in Saudi Arabia. RESULTS: 33 (60.0%) males,22 (40.0%) females, median age at diagnosis 68 months. Pilocytic astrocytoma was the most common pathological diagnosis 42 (76.4%) location of tumor was Infratentorial in 30 patients (54.0%) and Supratentorial in 24 patients (43.2%), 19 patients (34.6%) had total surgical excision, 10 (18.2%) subtotal resection, 20 (36.4%) partial excision and 6 (10.9%) had biopsy only; After initial Surgery 30 patients (54.5%) required adjuvant chemotherapy of whom 14 patients (46.7%) experienced a treatment failure event, 25 patients (45.5%) who were initially observed post surgery 6 patients (24%) of them had relapse /progression and required further therapy. Only 2 patients (3.6%) received radiotherapy due to uncontrolled progression first line chemotherapy carboplatin and vincristine (CV) regimen was tolerated, Carboplatin allergic reactions developed in 21.1% of patients. Median follow-up of 6.49 years, the median time of relapse/ progression was 2.85 years The 5-year overall survival (OS) rates and progression free survival for all patients were 92.2 %, and 63.3% respectively. This study was to document the outcome of pediatric LGG in Saudi Arabia and to serve as a guideline for the future management with incorporation of molecular studies on pediatric LGGs which may help improve the outcome for Saudi children with LGG.
LGG-19. SPINAL LOW-GRADE GLIOMAS IN CANADIAN CHILDREN: A MULTI-CENTRE RETROSPECTIVE REVIEW
Authors: Coltin Hallie , Benipal Savvy , Rassekh S Rod , Nobre Liana Figueiredo , Bennett Julie , Tabori Uri , Wilson Bev , Mehta Vivek , Beaudoin Wendy , Zelcer Shayna , Cheng Sylvia , Hukin Juliette , Hawkins Cynthia , Bouffet Eric , Johnston Donna
Published: December 2020

PURPOSE

Primary spinal low-grade gliomas (LGGs) are rare, can be difficult to treat, and can result in significant morbidity. The management of pediatric spinal LGGs remains controversial.

METHODS

A national multi-centre retrospective review of spinal LGGs diagnosed in children less than 18 years of age between 1990–2015 was undertaken to examine the clinical features, pathological subtypes, and treatment outcomes.

RESULTS

Forty-three patients from five institutions were included. The median age of diagnosis was 5.2 years. All patients were symptomatic at diagnosis. Forty-four percent of patients were diagnosed at least 6 months after symptoms developed. Two patients had metastatic disease at diagnosis. The most common histology was pilocytic astrocytoma (48.8%). Molecular information was available for 15/43 patients: 6 patients had BRAF fusions and 4 patients had BRAF V600E mutations. Gross-total resection was achievable in only 6 patients. Twenty-seven patients were treated with surgery-only and the others received chemotherapy and/or focal radiation. Eleven patients were irradiated. No patients were registered in clinical trials for first-line therapy. Twenty-three patients experienced relapse or progression. Patients were followed for a median of 8.3 years (range, 0.5–20.4 years). Five-year progression-free survival (PFS) and overall survival (OS) rates were 48.3% (95% CI, 32.3% to 62.5%) and 89.7% (95% CI, 74.6% to 96.1%) respectively.

CONCLUSION

There is significant heterogeneity in surgical outcomes and treatment modalities of pediatric spinal LGGs. The PFS and OS rates remain suboptimal, likely due to tumor location. The low clinical trial enrollment rate highlights the paucity of available trials for spinal LGGs.
LGG-20. CLINICAL FEATURES AND TREATMENT RESULTS FOR PEDIATRIC OPTICO-HYPOTHALAMIC ASTROCYTOMA
Authors: Yoshimoto Koji , Hata Nobuhiro , Higa Nayuta , Yonezawa Hajime , Uchida Hiroyuki , Oyoshi Tatsuki , Mizoguchi Masahiro
Published: December 2020

Current consensus for the treatment of optico-hypothalamic astrocytoma (OHA) is a chemotherapy-first policy, limiting the role of surgery for histopathological diagnosis and partial decompression. However, a subgroup of OHA patients show resistance to chemotherapy and have a worse prognosis. In this study, we retrospectively analyzed our clinical experiences of the treatment of patients with OHA in two university hospitals. We have extracted and analyzed the medical charts of 15 pediatric OHA patients treated in two university hospitals since 1990. NF-1-associated OHA patients were excluded. Patient ages ranged from 10 months to 21 years (median 7 years). Out of 15 cases, 12 patients had a tumor larger than 3 cm and classified as Dodge 3. The final histopathological diagnosis was pilocytic astrocytoma in 13 cases. Three patients with tumors classified as Dodge 1 or 2 show good prognosis only by biopsy or partial resection. However, regarding Dodge 3 tumor, patient prognosis is worse regardless of chemotherapy and radiotherapy. After the initial surgery, chemotherapy was administered in 11 cases and radiotherapy in 5 cases. Multiple surgeries are needed for tumor control in 7 patients. Four patients died of tumor progression or treatment-associated complications. When the initial tumor is large enough to cause neurological deterioration, a chemotherapeutic tumor suppressive effect might be limited in a subset of large OHA cases. Therefore, it is important to consider the proper timing of safe surgical decompression in the early phase when a large tumor does not respond to chemotherapy.
LGG-21. MR-GUIDED LASER INTERSTITIAL THERMAL THERAPY FOR UNRESECTABLE AND SYMPTOMATIC PEDIATRIC LOW GRADE GLIOMA
Authors: Kram David , Benjamin-Eze Jessica , Strowd Roy , Tatter Stephen
Published: December 2020

BACKGROUND

Pediatric low-grade gliomas (LGG) not amenable to resection, while often indolent, represent a significant source of cancer-related morbidity and an unmet therapeutic need. Standardly, these patients are treated with sequential lines of chemotherapy, while delaying as long as possible radiation. Magnetic resonance-guided laser interstitial therapy (LITT) is a minimally invasive procedure that utilizes real-time MR thermography to ablate brain lesions.

METHODS

A 15-year-old girl was diagnosed with a suprasellar, hypothalamic LGG, BRAF V600E mutation positive. The tumor was unresectable, and due to progressive vision loss and headaches, the patient underwent treatment. Despite sequential trials of thioguanine/procarbazine/lomustine/vincristine, carboplatin/vincristine, dabrafenib, and combination dabrafenib/trametinib, the patient continued to experience debilitating headaches, malnutrition, school absenteeism, and overall poor quality-of-life. Using real-time, sequential MRI-thermometry and the Neuroblate cooled directional laser catheter, the bulk of the enhancing tumor was heated to a killing temperature.

RESULTS

At 1-year post LITT, the patient’s symptoms were dramatically improved, including greatly improved headaches, malnutrition, school absenteeism, and overall quality of life. LITT was generally well tolerated, though the patient had slight progressive left homonymous hemianopia, thought secondary to LITT impact on the optic tracts. The tumor progressively shrank over the year post-LITT to a peak of 42% volume reduction.

CONCLUSION

We report a case of a pediatric patient with an unresectable low grade glioma who underwent LITT with excellent clinical and radiographic effects. LITT should be considered for children with unresectable and morbid LGGs that fail to respond to more conventional therapies.
LGG-33. ISOMORPHIC DIFFUSE GLIOMA HAS RECURRENT GENE FUSIONS OF MYBL1 OR MYB AND CAN BE DISTINGUISHED FROM OTHER MYB/MYBL1 ALTERED GLIOMAS BASED ON A DISTINCT MORPHOLOGY AND DNA METHYLATION PROFILE
Authors: Wefers Annika K , Stichel Damian , Schrimpf Daniel , Sahm Felix , von Deimling Andreas , Blumcke Ingmar , Jones David T W , Capper David
Published: December 2020

Isomorphic diffuse glioma (IDG) was first described in 2004 as an epilepsy-associated supratentorial diffuse glioma with low cellularity, low proliferation and very monomorphic tumour cells. Most patients had seizures since childhood but were operated on as adults. To study the position of these lesions among brain tumours we histologically, molecularly and clinically analysed 26 histologically typical IDGs. Tumour cells were GFAP-positive, MAP2-, OLIG2- and CD34-negative and the nuclear ATRX-expression was retained. Proliferation was very low. Sequencing of 24 cases revealed an IDH-wildtype status. Cluster analyses of DNA methylation data showed that IDG has a DNA methylation profile distinct from those of different glial/glio-neuronal brain tumours and normal hemispheric tissue. About half of IDGs had copy number alterations of MYBL1 or MYB (13/25) and half of the cases analysed by RNA-sequencing had gene fusions of MYBL1 or MYB with various gene partners (11/22), often associated with an increased RNA-expression of the respective MYB-family gene. Integrating all data available, 77% of IDGs had either MYBL1 (54%) or MYB (23%) alterations. All patients had a good outcome and most were seizure-free after surgery. In summary, we show that isomorphic diffuse glioma is a distinct benign tumour in the family of MYB/MYBL1-altered gliomas. DNA methylation analysis is very helpful for their identification. More recent analyses of a large cohort of MYB/MYBL1-altered brain tumours suggest the presence of a third methylation group that primarily contains paediatric cases and seems to be distinct from IDG and angiocentric gliomas. Further histological, molecular and clinical analyses are ongoing.
LGG-34. CLINICAL AND MOLECULAR CHARACTERIZATION OF A MULTI-INSTITUTIONAL COHORT OF PEDIATRIC SPINAL CORD LOW-GRADE GLIOMAS
Authors: Grob Sydney , Nobre Lianna , Davies Kurtis , Ryall Scott , Aisner Dara , Hoffman Lindsey , Zahedi Shadi , Morin Andrew , Nellan Anandani , Green Adam , Foreman Nicholas , Vibhakar Rajeev , Hankinson Todd , Handler Michael , Hawkins Cynthia , Tabori Uri , Kleinschmidt-DeMasters B K , Levy Jean Mulcahy
Published: December 2020

BACKGROUND

The MAPK/ERK pathway is involved in cell growth and proliferation, and mutations in the BRAF paralog of this pathway have made it an oncogene of interest in pediatric cancer. Previous studies have identified that BRAF mutations as well as BRAF-KIAA1549 fusions are common in intracranial low-grade gliomas (LGGs). Fewer studies have tested for the presence of these genetic aberrations in spinal LGGs. The aim of this study was to better understand the prevalence of BRAF and other genetic aberrations in spinal LGG.

METHODS

We analyzed 46 spinal LGGs from children age 1–25 years from two institutions, Children’s Hospital Colorado (CHCO) and The Hospital for Sick Children (Sick Kids) for the presence of BRAF fusions or mutations. Data was correlated with clinical information. A 67 gene panel additionally screened for other possible genetic abnormalities of interest in the patient cohort from CHCO. In the Sick Kids cohort, BRAFV600E was tested for by ddPCR and IHC while BRAF fusions where detected by FISH, RT-PCR or Nanostring platform.

RESULTS

Of the 31 patient samples who underwent fusion analysis, 13 (42%) harbored the BRAF-KIAA1549 fusion. Overall survival (OS) for patients confirmed positive for BRAF-KIAA1549 was 100% compared to 76% for fusion negative patients. Other mutations of interest were also identified in this patient cohort including BRAFV600E, STK11, PTPN11, H3F3A, APC, TP53, PIK3CA (polymorphism), FGFR1, and CDKN2A deletion.

CONCLUSION

BRAF-KIAA1549 was seen in higher frequency than BRAFV600E or other genetic aberrations in pediatric spinal LGGs and trends towards longer OS although not statistically significant.
LGG-36. DESMOPLASTIC INFANTILE GANGLIOGLIOMA (DIG) WITH A PPP1CB-ALK FUSION IN A 6-YEAR-OLD GIRL
Authors: McDonald William , Nagib Mahmoud , Jenkins Robert , Ida Cristiane , Halling Kevin , Skrypek Mary , Bendel Anne
Published: December 2020

Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are benign glioneuronal tumors that typically occur in infants, involve the superficial cerebral cortex, and have an excellent prognosis. DIA/DIG are a distinct molecular entity based on DNA methylation profiling. BRAF600 mutations are frequently reported in DIG/DIA. A recent comprehensive genetic analysis of infantile hemispheric gliomas identified 2 unique groups: group 1 harbored alterations in the receptor tyrosine kinase (RTK) genes ALK, ROS1, NTRK, and MET and group 2 harbored alterations in the RAS/MAPK pathway. We report a case of a 6.5-year-old girl who presented with seizures and right homonymous hemianopia. MRI of her brain demonstrated a large cystic/solid left hemispheric mass with remodelling of the overlying skull, consistent with a long-standing process. She underwent a gross total resection (GTR) and pathology demonstrated a DIG with a PPP1CB-ALK gene fusion (exon 5 to exon 20) identified by RNA sequencing. She remains disease free 12 months following GTR. A literature review identified 4 reported cases of pediatric brain tumors with PPP1CB-ALK gene fusions including: a 3-month-old with a hemispheric high-grade glioma which recurred 4 years later and pathology showed mature ganglioglioma, with both tumors showing the identical PPP1CB-ALK gene fusion; a 10-month-old infant with a hemispheric low-grade glioma; an infant with a “congenital” hemispheric high-grade glioma; and a child with an astrocytoma with no further clinical data. PPP1CB-ALK gene fusion appears to be a rare oncogenic driver in gliomas of infancy, including DIG.
LGG-40. NATURAL COURSE AND MANAGEMENT OF SMALL ASYMPTOMATIC LESION SUSPECTED OF LOW-GRADE GLIOMA IN CHILDREN
Authors: Muroi Ai , Tsurubuchi Takao , Kohzuki Hidehiro , Suzuki Ryoko , Fukushima Hiroko , Yamaki Yuni , Ishikawa Eiichi , Matsumura Akira
Published: December 2020

OBJECTIVE

The natural course of incidentally discovered small intracranial lesions has not been well discussed. Surgical intervention, including resection and biopsy, could be achieved if the lesion is growing. We present 13 cases with incidentally found, small non-enhancing lesions without related symptoms.

METHODS

We retrospectively reviewed a series of 13 children with T1 hypointense and T2 hyperintense intracranial lesions less than 20 mm in diameter without enhancement. We excluded the patients with NF-1 or Tuberous sclerosis.

RESULTS

Most patients underwent MRI for headache unrelated to the lesions. All cases were located supratentorially. The median age of the patients at the initial examination was 8.9 years (range, 2.2–14.6). Of these children, 2 patients (15.3%) underwent surgery because of progression on follow-up MR images. The pathological diagnosis was compatible with diffuse astrocytoma. Patients were followed for a median of 55 months (range, 11–87) and the overall survival rate was 100%. No patient experienced increase in size after 3 years of follow-up.

CONCLUSIONS

In most patients with small intracranial lesions, the lesions remained stable and conservative management was appropriate. However, in a few cases, the lesions changed in size or quality and surgical intervention was necessary. Long-term follow-up at least 3 years is mandatory.
LGG-46. MOLECULAR CHARACTERIZATION OF HEMISPHERIC LOW-GRADE GLIOMAS IN CHILDREN
Authors: Mišove Adéla , Krsková Lenka , Sumerauer David , Zámečník Josef , Váňová Kateřina , Starý Jan , Perníková Ivana , Vícha Aleš , Libý Petr , Tichý Michal , Táborský Jakub , Kynčl Martin , Zápotocký Michal
Published: December 2020

BACKGROUND

Heterogeneous pathology in hemispheric low-grade gliomas (hemLGG) stress the importance of molecular testing in terms of prognosis prediction and targeted therapy options.

METHODS

Demographic data was collected and targeted genomic approach was employed in the single institutional study. RT-PCR was used to screen for KIAA1549-BRAF fusion and FGFR1 tyrosine-kinase domain duplication (FGFR1-ITD). Direct sequencing evaluated point mutations (BRAF ex15 and ex11, FGFR1 ex12 and ex14). Samples with no detected alteration were subjected to panel RNA-sequencing (FusionPlex Archer Diagnostics).

RESULTS

Within 2000–2019 were diagnosed 76 patients with hemLGG (median age 11.1y, range 0.0y–18.5y) comprising predominantly of ganglioglioma, dysembryoplastic neuroepithelial tumors, and diffuse astrocytoma. 40 % of hemLGG were characterized by BRAF alterations with over 2/3 of those cases harboring BRAF point mutations (two BRAFex11, 12 BRAFV600E). Notably, BRAF fusions were uncommon and detected only in six patients (two KIAA-BRAF fusion, two minor oncogenic BRAF variants, two non-KIAA BRAF fusion). 25 % of alterations were found in genes for receptor tyrosine kinases, consisting of seven patients with FGFR1-ITD, three FGFR2/3 fusions, two FGFR1 mutations, two ALK fusions, and one ROS fusion. Out of MAP kinase pathway, the most frequent alteration was IDH1 mutations (n=9). Two angiocentric gliomas were characterized by MYB-QKI fusion.

CONCLUSION

Targeted sequencing combined with RNA-sequencing is feasible to establish molecular diagnosis in majority of cases and reveal new and rare alterations. Significant prevalence of non-BRAF alterations explains heterogeneity among hemLGG.
LGG-57. SIGNALLING MECHANISMS IN PAEDIATRIC LOW-GRADE GLIOMA
Authors: Patel Ankit , Jones Tania , Woodward Lewis , Dokal Arran , Rajeeve Vinothini , Cutillas Pedro , Stone Thomas , Jacques Thomas , Sheer Denise
Published: December 2020

Paediatric low-grade gliomas (pLGGs) constitute the largest group of childhood CNS tumours. They often cause significant disability and morbidity, despite their indolent growth and the good survival rate of patients. The most common genetic alterations in these tumours, KIAA1549:BRAF fusion and BRAFV600E mutation, lead to abnormal activation of MAPK signalling. The central role of this pathway in pLGG development is emphasized by the occasional presence of other MAPK-activating alterations such as RTK mutations. It is not known how these different aberrations can induce the variety of clinical phenotypes seen in pLGG. Here, we compared pilocytic astrocytomas (PAs) containing the KIAA1549:BRAF fusion with glioneuronal tumours (GNTs) containing the BRAFV600E mutation, to identify differentially activated downstream targets of the MAPK pathway. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used as a multi-proteomic approach. Kinase Set Enrichment Analysis (KSEA) using PhosphositePlus and NetworkIN was used to determine relative enrichment of kinase activity in the tumours compared to healthy control brain tissue. Significant similarities and differences were found in the two tumour types. For example, more robust MAPK activation was found in the GNTs than in PAs. However, while PI3K/AKT1/mTOR signalling was active in both PAs and GNTs, there was statistically higher activation in the PAs. In both tumour types, there was significant reduction in casein kinase 2 activity, which likely affects nuclear translocation of ERK and, in turn, alters the range of its phosphorylated substrates. We will present these data together with transcriptomics to further characterise the downstream targets of these genetic alterations.
LINC-01. COMPLIANCE TO FOLLOW UP IN PEDIATRIC PATIENTS WHO HAVE RECEIVED CRANIOSPINAL IRRADIATION
Authors: Pyone Khin , Tun Thwe , Win Yin , Thinn Aye , Win Khin , Hnin Tint , Khaing Aye
Published: December 2020

OBJECTIVE

Attendance to follow-up after completion of cancer treatment is understudied area. Pediatric cancer patients have sequelae of illness or treatment. Many have no symptom immediately after completion of treatment. Long term follow-up is important to access disease control, early diagnosis of recurrence, second cancer and treatment-related morbidities. Purpose of this study was to evaluate the compliance to follow-up in pediatric patients treated with craniospinal irradiation (CSI).

METHODS

This was retrospective review of follow-up in pediatric neuro-oncology patients who received (CSI) from January 2017 to June 2018 in the Radiotherapy Department of Yangon General Hospital, Myanmar. RESULT: Twenty-three patients received CSI; majority (43%) were medulloblastoma. Median age was 7.5 years (3–17 years). Only seven patients (30.4%) were attended to follow-up more than 6 months after completion of treatment. More than two-thirds of patients (n=16,69.6%) were lost to follow-up. Patients in active follow-up were diagnosed and treated at earlier age below 10years (n=5,21.7%). Demographically, 5 patients (22%) were living in the region around tertiary hospital. Sixteen patients (69.6%) from rural area had limited transportation and difficulty for accommodation in which they were treated. In socioeconomic points, 18 parents (78.2%) had poor education and financial status, lack of understanding about disease, treatment, long-term effects and follow-up.

CONCLUSION

Although this was limited data in CSI patients only, loss to follow-up after 6 months was high. We need to evaluate in all pediatric cancer patients and collaborate to provide financial support, childcare centres for lodging, transportation and health education to promote compliance to follow-up.
LINC-08. INCREASED TREATMENT TOXICITIES AND INFERIOR OUTCOMES IN UNDERNOURISHED CHILDREN WITH BRAIN TUMOURS
Authors: Prasad Maya , Chheda Ekta , Chinnaswamy Girish , Gupta Tejpal , Krishnatry Rahul , Vora Tushar , Godashastri Jayant
Published: December 2020

BACKGROUND

Children on treatment for brain tumours are known to be at high risk of undernutrition, the impact on outcome and toxicity is not well understood.

METHODS

Retrospective audit of children(<18 years)diagnosed January 2017-December 2018 with embryonal brain tumours (medulloblastoma, primitive neuro-ectodermal tumors, pinealoblastoma, atypical teratoid/rhabdoid tumour) and treated at our centre. Data was retrieved from case records and electronic medical records. Nutritional status(NS) was defined as per World Health Organization (WHO) into severe malnutrition (SAM),moderate malnutrition (MAM),well nourished (WN) and overweight. Undernutrition(UN) was defined as SAM/MAM.Toxicity was documented till end of treatment,defined as treatment delay>1week,significant infection or toxic death.

RESULTS

Of 124 eligible patients who received entire chemotherapy at our centre, NS data was available in 73 at diagnosis and 58 at follow-up. At diagnosis-29,16,26 and 2 and at follow-up-20,16,22 and 0 were SAM,MAM,WN and overweight. During treatment, weight gain was documented in 26%, stable weight in 55% and weight loss in 19%. Those UN at diagnosis had worse outcomes at follow-up with 70% alive in remission compared to 88% of WN(p-0.14). There was increased toxicity in UN group(50%) compared to WN(24%),p-0.04.All 3 toxic deaths were in UN. Those who lost weight during treatment had higher toxicities(70%) compared to those with stable weight (30%)or weight gain(20%),p-0.02.

CONCLUSIONS

In spite of nutritional intervention, children on treatment for brain tumours tend to lose weight. Increased treatment toxicities and inferior outcomes in undernourished children with brain tumours necessitates proactive and aggressive nutritional monitoring and intervention.
LINC-11. NEUROPATHOLOGY REVIEW OF LATIN AMERICAN CHILDHOOD AND ADOLESCENT BRAIN TUMOR PATIENTS: A MULTI-NATIONAL, MULTI-DISCIPLINARY PEDIATRIC NEURO-ONCOLOGY TELECONFERENCE EXPERIENCE
Authors: Osorio Diana S , Pierson Christopher R , Lassaletta Alvaro , la Madrid Andres Morales , Qaddoumi Ibrahim , Bartels Ute , Boue’ Daniel R , Finlay Jonathan L
Published: December 2020

BACKGROUND

Pediatric brain tumor classification has undergone significant evolution over the last decade requiring a high-level of expertise and diagnostic techniques. Such advances have created challenges for pathologists particularly in low-to-middle income countries (LMIC). We conduct weekly pediatric neuro-oncology teleconferences linking global pediatric neuro-oncologists from high-income countries (HIC) to review patients with pediatric subspecialists from Latin America.

METHODS

Three to five patients are discussed weekly and second neuropathology review is offered when a high-level of suspicion emerges of a questionable diagnosis based on clinical and radiographical information. Nationwide Children’s Hospital (NCH) provides second neuropathology review at no cost to institutions in Latin America that fulfill these criteria.

RESULTS

From July 2015 to December 2019 NCH reviewed 54 pathology samples from eleven Latin American countries. Of these, 33 (61.1%) cases resulted in diagnostic changes, of which 28 (51.8%) were significant, impacting treatment plans and overall patient outcomes. The remaining 21 (38.9%) confirmed institutional diagnosis; however, in eight of these 21 cases additional molecular information and/or further tumor subtyping unavailable in their home country at the time (eg: BRAF, RELA-fusion, medulloblastoma subtyping) was provided.

CONCLUSIONS

This study highlights the importance of centralized pathology review by institutions with the proper equipment, infrastructure and expertise in pediatric neuropathology. Furthermore, this documents the beneficial impact of teleconferencing for subspecialists in LMIC who must treat a wide variety of pediatric cancers with few resources and support. Additionally, our findings underscore the need for pediatric subspecialty training in LMIC.
LINC-14. TREATMENT OF PEDIATRIC CNS TUMORS IN ARMENIA. 10 YEARS OF EXPERIENCE IN A 29 YEARS OLD RESOURCE-LIMITED SETTING
Authors: Harutyunyan Martin , Sargsyan Lilit , Iskanyan Samvel , Hakobyan Lusine , Papyan Ruzanna , Tamamyan Gevorg , Bedirian Karen , Danielyan Samvel , Tananyan Armen , Avagyan Manushak , Karapetyan Nune , Bardakhchyan Samvel
Published: December 2020

BACKGROUND

Pediatric CNS tumors are the most common solid childhood malignancies with many challenges facing optimal outcome due to multimodality complex therapies, abandonment, and long-term morbidity. In our three-decades young, country the field of neuro-oncology is in its infancy. MATERIALS: The aim of our study is to assess incidence, epidemiology and treatment outcomes of children diagnosed and treated with CNS tumors within the last 10 years (2009–2019) in the Chemotherapy Clinic of “Muratsan” Hospital Complex of Yerevan State Medical University.

RESULTS

During these periods 20 patients with CNS tumors were treated in our clinic. 13 patients (65%) were diagnosed with medulloblastoma (2 patients were infants), two patients (10%) with optic pathway glioma, and 5 patients each with pilocytic astrocytoma, ATRT, ETANTR, DIPG, and glioblastoma. Five patients (3 patients with medulloblastoma, 1 patient with pilocytic astrocytoma, 1 patient with ATRT) had metastatic disease at the time of diagnosis. Seventeen patients (80%) had undergone surgery, 8 patients with medulloblastoma received chemo-RT with vincristine. Median follow up time was 15.5 months (range 5–94). Twelve patients (60%) are alive without evidence of disease. 5 patients had disease progression and three patients relapsed. From them, 3 patients died. Long-term survivors are mainly standard risk medulloblastoma patients. All medulloblastoma patients were treated according to HIT-MED guidelines.

CONCLUSION

Here we report about the pediatric brain tumors of one of the main pediatric oncology units in Armenia for a period of 10 years. The numbers are quite small for firm conclusions, but it shows the emerging need for further research.
LINC-17. SIROLIMUS AS AN ALTERNATIVE TO SURGICAL RESECTION OF PEDIATRIC TUBEROUS SCLEROSIS COMPLEX-ASSOCIATED BILATERAL SUBEPENDYMAL GIANT CELL ASTROCYTOMAS: AN AFFORDABLE OPTION FOR PATIENTS FROM LOW-MIDDLE INCOME COUNTRIES
Authors: Orduña Patricia
Published: December 2020

Subependymal giant cell astrocytomas (SEGA) may lead to significant neurological morbidity in children diagnosed with tuberous sclerosis complex (TSC). Surgical resection is warranted for SEGAs demonstrating continuous growth, causing hydrocephalus and increased intracranial pressure. mTOR inhibitors (sirolimus and everolimus) are alternatives to surgery and have shown efficacy in stabilizing and shrinking SEGAs. Everolimus showed stronger evidence in efficacy, but its cost poses a limitation for this treatment among patients from low-middle income countries. We explored sirolimus as a potentially more cost-effective alternative in our setting. We present a 10-year-old Filipino child with TSC admitted due to headache, vomiting, and increased sleeping time. Neuroimaging revealed large bilateral SEGAs involving the frontal horns and foramina of Monro, causing moderate obstructive hydrocephalus. Surgical excision was offered, but parents opted for medical treatment. Bilateral posterior parietal ventriculoperitoneal shunts were inserted to decrease intracranial pressure. Due to the cost of everolimus, the patient was started on sirolimus at 1mg/m2/day. Imaging done 6 months after initiating therapy demonstrated significant decrease in size of both SEGAs (right: 82.5%, left: 64.1%). Sirolimus levels were maintained at 15.7ng/ml and minimal elevations on cholesterol and triglyceride levels were observed and treated with simvastatin. Results of this case and review of related data suggest that sirolimus can be used as a conservative approach in inducing regression of large bilateral SEGAs, and an affordable alternative to everolimus for pediatric TSC patients from low-middle income countries. Prospective studies and clinical trials are needed to further establish its efficacy, safety and cost-effectiveness in our setting.
LINC-24. CHARACTERISTICS OF PEDIATRIC BRAIN TUMORS AT DEPARTMENT OF CHILD HEALTH FACULTY OF MEDICINE UNIVERSITAS INDONESIA-DR. CIPTO MANGUNKUSUMO TERTIARY GENERAL HOSPITAL, JAKARTA, INDONESIA
Authors: Widodo Dwi Putro , Mangunatmadja Irawan , Siregar Marsintauli , Pusponegoro Hardiono , Handryastuti Setyo , Soebadi Amanda , Rafli Achmad
Published: December 2020

Brain tumors are still the second leading cause of death among cancers in children. Based on data from National Brain Tumor Society (2019), in United States, there are 28.000 children living with brain tumor with varied clinical, radiological, and histopathological features. The most prevalent children’s brain tumor types in US are gliomas (ependymal tumors, pilocytic astrocytomas) and embroyonal tumors, including medulloblastoma. From 1993–1994 at Department of Child Health Faculty of Medicine Universitas Indonesia-Dr. Cipto Mangunkusumo Tertiary General Hospital, Jakarta, Indonesia, there are 19 patients with brain tumors hospitalized with most of patients with astrocytoma 8 patients (42%), 4 patients (21%) medulloblastoma, 2 patients (11%) neuroblastoma, 2 patients (11%) ependymoma, 2 patients (11%) craniopharyngioma, and one patient (4%) meningioma. Retrospective cohort study (2010–2015) with subjects 100 children revealed that based on the radiographs, the brain tumors were located mostly in the cerebellum (24%) and the suprasellar region (10%); based on the histopathology, the most common types of brain tumor were astrocytomas (18%), medulloblastoma (21%), and gliomas (17%). The most common symptom of brain tumors was headache and impaired vision. Survival patients with brain tumors for 5 years in the age group aged 3 years and above was better than that in children aged under 3 years (60% vs 55% and 17% vs 14%). This report can serve as one of basic data for profile children’s brain tumors in Indonesia. Keywords: brain; tumor; children; survival; Indonesia
LINC-25. BRAF ABERRATIONS IN PEDIATRIC PILOCYTIC ASTROCYTOMAS (PCAs): PREVALENCE AND IMPACT ON CLINICAL OUTCOME
Authors: Ramanathan Subramaniam , Prasad Maya , Vora Tushar , Gurav Mamta , Sahay Ayushi , Sahu Arpita , Moiyadi Aliasgar , Shetty Prakash , Goda Jayant Sastri , Krishnatry Rahul , Gupta Tejpal , Epari Sridhar , Chinnaswamy Girish
Published: December 2020

BACKGROUND

Increasing knowledge on pilocytic astrocytoma (PCA) biology now points towards an aberration in BRAF/MAPK/ERK pathway which has both diagnostic and therapeutic implications. This study was done to note the impact of BRAF aberrations on clinical outcome in childhood PCA.

METHODS

FFPE tissues of all childhood PCA diagnosed during 2011–2017 were evaluated for BRAFV600E mutation by Sanger sequencing and KIAA1549 fusion transcripts (16–9;15–9;16-11) by reverse transcriptase polymerase chain reaction. Children undergoing gross tumor resection received no adjuvant treatment. Unresectable tumors (only biopsy) and NF-1 associated PCAs, were treated if clinically indicated. Only patients with documented therapy details/followup were included for analysis. STUDY

RESULTS

Ninety-eight patients (median age-7.7yrs; boy:girl ratio-1.4) were included. Major sites were: Cerebellum-37(38%), 3rd Ventricle-26(27%), Cerebrum-15(15%). While BRAFV600E mutation was noted in 7/89(8%) specimens, BRAF-fusions were found in 34/85(40%). Following surgery/biopsy, 23(24%) and 21(22%) received adjuvant chemotherapy and radiotherapy respectively. The 1-year/3-year/5-year-EFS of the overall cohort was 90.7%/81.3%/67.4% respectively. Cerebellar tumors did better vis-à-vis other sites(5yr-EFS:74.3% v/s 66.4%;p=0.403). The 5yr-EFS of BRAF-fusion positive tumors (34), tumors without any BRAF aberration (40) and BRAFV600E mutant tumors (7) was 84.8%/ 69.6%/ 42.9% (p=0.215).

CONCLUSIONS

BRAF-fusion and BRAFV600E mutation were associated with good and poor outcomes respectively. Lack of statistical significance could be attributed to use of radiation as planned therapy in patients from earlier years. Data on BRAF aberrations in PCAs aids decision making regarding adjuvant therapy and choosing appropriate salvage-therapy especially in relapsed/refractory PCAs.
LINC-29. IMPACT OF RELA FUSION ON OUTCOMES OF CHILDHOOD SUPRATENTORIAL EPENDYMOMAS (ST-EPEN)
Authors: Chinnaswamy Girish , Ramanathan Subramaniam , Prasad Maya , Vora Tushar , Sahay Ayushi , Gurav Mamta , Sahu Arpita , Moiyadi Aliasgar , Shetty Prakash , Goda Jayant Sastri , Krishnatry Rahul , Gupta Tejpal , Epari Sridhar
Published: December 2020

BACKGROUND

Ependymomas are heterogenous group of tumours with variable clinical course and diverse molecular features. RELA fusion status has been reported to have prognostic impact in ST-EPEN. Our retrospective study analysed the prevalence and clinical impact of RELA fusion in childhood ST-EPEN at our centre. STUDY

METHODS

FFPE tissues of all childhood ST-EPEN diagnosed during 2011–2017 were evaluated for RELA fusion 1/2 by RT-PCR. Children were treated as per guidelines by the Neuro-oncology multidisciplinary team. Outcomes were correlated with RELA fusion, histological features and immunohistochemical parameters(L1CAM expression and Mib-1 index). Only patients with therapy details were included.

RESULTS

A total of 37 patients(0–50 years) with ST-EPEN were included(median age-10.2 years; boy:girl ratio-1.4:1)for analysis. Histological grade II, II/III and III was seen in 4(11%),2(5%) and 31(84%) patients respectively. Mib-1 index was assessable in 33 patients of which, 9 patients (24%) had a Mib-1 index >20%. RELA fusion was detected in 13(35%)tumors. The 3-year and 5-year EFS/OS of the overall cohort was 64.2%/83.6% and 60.1%/73.1% respectively. The 3-year/5-year EFS of RELA-positive tumors was inferior compared to RELA-negative tumours (53.8%/36% v/s 62.6%/53.6%; p=0.391). The 3-year/5-year EFS of tumors expressing L1CAM versus negative-expression was comparable (61.1%/55%v/s59.8%/47.9%;p=0.44). Presence of Mib-1>20% correlated with inferior survival (5-year EFS:81.1%vs22.2%; p<0.01).

CONCLUSIONS

ST-EPEN with RELA fusion had trend towards increased relapse/progression. High Mib-1 correlated with poor survival. RELA fusion status needs to be studied in a larger cohort prospectively to confirm its clinical impact.