scholarly journals RARE-48. CHARACTERISTICS AND OUTCOME OF DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT): A SINGLE INSTITUTION EXPERIENCE

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii452-iii452
Author(s):  
Emily Owens Pickle ◽  
Ana Aguilar-Bonilla ◽  
Amy Smith
Keyword(s):  
Mapk Pathway ◽  
Clinical History ◽  
Mek Inhibitor ◽  
Glioneuronal Tumor ◽  
Unknown Etiology ◽  
Leptomeningeal Disease ◽  
Low Grade ◽  
Diffuse Leptomeningeal Glioneuronal Tumor ◽  
Braf Fusion ◽  
Chemotherapy Patients

Abstract Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare with an unknown etiology and unestablished incidence. Most frequently reported genetic alteration is KIAA1549-BRAF fusion. We present four DLGNT cases diagnosed between 2005–2018. Patient 1 is a female who presented with a 2-year history of back pain subsequently diagnosed with pilocytic astrocytoma. Re-imaging 3 months post-resection revealed a low grade glioneuronal tumor with BRAF duplication. Patient 2 is a female who presented with recurrent vomiting, dizziness, and hydrocephalus. The patient underwent biopsy which was consistent with oligodendrogliomatosis; no genetic analysis was done. Patient 3 is a male who presented with worsening headaches and intermittent vomiting. Approximately 5 months after resection, imaging showed leptomeningeal disease and further testing revealed KIAA1549-BRAF fusion and 1p deletion. Patient 4 is a male who presented with hydrocephalus. Imaging showed disseminated leptomeningeal enhancement without a dominant mass lesion; biopsy and clinical history confirmed the diagnosis. All four patients received chemotherapy, Patients 1 and 3 underwent radiation therapy, and Patient 3 received a MEK-inhibitor to which he had a great response. However, the patient was non-compliant and had PD which continued despite re-starting therapy. Patients 1, 2, and 3 have died of progressive disease; survival was Patient 1, 276 days, Patient 2, approximately 7 years and 8 months, and Patient 3, 2 years and 11 months. Patient 4 remains alive with disease 4.5 years from diagnosis. There is much to be learned about this rare, poorly understood disease but hope for improvement through therapeutic targeting of the MAPK pathway.

scholarly journals LGG-26. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) IN CHILDREN: DIFFERENT CLINICAL PRESENTATIONS AND OUTCOMES

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii371-iii371
Author(s):  
Andge Valiakhmetova ◽  
Ludmila Papusha ◽  
Ludmila Yasko ◽  
Alexander Druy ◽  
Alexander Karachunsky ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Braf Inhibitor ◽  
Complete Response ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Glioneuronal Tumor ◽  
Low Grade ◽  
Conventional Chemotherapy ◽  
Diffuse Leptomeningeal Glioneuronal Tumor ◽  
Braf Fusion

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.

DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR IN CHILDREN: MR CHARACTERISTICS, CLINICAL FEATURES AND OUTCOME. FOUR CLINICAL CASES

2021 ◽  
Vol 20 (1) ◽  
pp. 42-55
Author(s):  
A. F. Valiakhmetova ◽  
L. I. Papusha ◽  
A. V. Artemov ◽  
G. V. Tereshchenko ◽  
E. A. Sal’nikova ◽  
...  
Keyword(s):  
Fusion Gene ◽  
Molecular Genetic ◽  
Complete Response ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Glioneuronal Tumor ◽  
Molecular Testing ◽  
Genetic Characteristics ◽  
Diffuse Leptomeningeal Glioneuronal Tumor ◽  
Braf Fusion

Background. Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely rare entity first officially recognized in 2016 WHO classification of tumors of the central nervous system. Magnetic resonance imaging (MRI) of this tumor usually visualizes diffuse meningeal infiltration with contrast enhancement, with the presence of multiple small contrast‑negative cysts, visible mainly in the T2 images. The main molecular markers of DLGNTs include the KIAA1549-BRAF fusion gene, BRAF V600E substitution is less common.The aim of this work is to describe the manifestation of DLGNT, its neuroimaging and molecular genetic characteristics, the experience of using anti‑BRAF and anti‑MEK therapy.Materials and methods. In this article are described four cases of DLGNT. The first patient with the presence of the KIAA1549-BRAF fusion in the tumor tissue received a full course of SIOP‑LGG / 2004 chemotherapy (carbo‑ platin and vincristine), the stabilization of the disease on the MRI remains for 4 years after completion of treatment. Second patient with KIAA1549-BRAF fusion gene in tumour tissue received MEK inhibitor trametinib as first line of treatment with the stabilization of the disease on control MRI which last for 2 years. A third patient with a mutation in the BRAF V600E gene. After disease progression on standard chemotherapy (carboplatin and vincristine) according to the SIOP‑LGG / 2004 protocol, anti‑BRAF therapy with vemurafenib was prescribed. After 10 months on MRI a complete response was recorded, which persists during the drug intake for 2.5 years. In the fourth patient, no molecular genetic aberrations were detected; a refractory / progressive course of the dis‑ ease was noted. To date, the stabilization of the disease is recorded on the fourth line of chemotherapy (everoli‑ mus and temozolomide).Conclusion. Given the rarity of this tumor and the lack of consensus about therapy, despite the limited number of observations, our experience allows us to recommend molecular testing of DLGNT to detect activating events in the BRAF gene, as well as consideration of anti‑BRAF / MEK therapy if either the BRAF V600E mutation is de‑ tected or KIAA1549-BRAF fusion.

scholarly journals LGG-14. MULTI-OMIC ANALYSIS OF MAPK ACTIVATION IN PEDIATRIC PILOCYTIC ASTROCYTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii368-iii368
Author(s):  
Romain Sigaud ◽  
Florian Selt ◽  
Thomas Hielscher ◽  
Nina Overbeck ◽  
Diren Usta ◽  
...  
Keyword(s):  
Target Genes ◽  
Profile Analysis ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Low Grade ◽  
Brafv600e Mutation ◽  
Braf Fusion ◽  
Mapk Inhibitors ◽  
Data Layers

Abstract 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.

scholarly journals LGG-17. SYNERGISTIC ACTIVITY OF MAPK INHIBITOR CLASSES REVEALED BY A NOVEL CELL-BASED MAPK ACTIVITY PEDIATRIC LOW-GRADE GLIOMA ASSAY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii369-iii369
Author(s):  
Diren Usta ◽  
Romain Sigaud ◽  
Juliane L Buhl ◽  
Florian Selt ◽  
Viktoria Marquardt ◽  
...  
Keyword(s):  
Cell Lines ◽  
Mapk Pathway ◽  
Braf V600e ◽  
Vector System ◽  
Luciferase Reporter ◽  
Low Grade ◽  
Brafv600e Mutation ◽  
Pathway Activity ◽  
Combination Treatments ◽  
Braf Fusion

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, > RAFi/ERKi > 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.

Unusual high-grade features in pediatric diffuse leptomeningeal glioneuronal tumor: comparison with a typical low-grade example

2017 ◽  
Vol 70 ◽  
pp. 105-112 ◽  
Author(s):  
Katherine E. Schwetye ◽  
Akash P. Kansagra ◽  
James McEachern ◽  
Robert E. Schmidt ◽  
Karen Gauvain ◽  
...  
Keyword(s):  
Glioneuronal Tumor ◽  
Low Grade ◽  
High Grade ◽  
Diffuse Leptomeningeal Glioneuronal Tumor

scholarly journals LGG-17. CLINICAL OUTCOME OF PEDIATRIC LOW GRADE GLIOMA WITH POSITIVE BRAF-FUSION TREATED WITH MEK INHIBITOR

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i35-i35
Author(s):  
T L Ku Dennis ◽  
Anthony P Y Liu ◽  
Eric Fu ◽  
Chung-Wing Luk ◽  
Jeffrey P W Yau ◽  
...  
Keyword(s):  
Partial Response ◽  
Skin Reaction ◽  
Treatment Option ◽  
Clinical Symptoms ◽  
Mek Inhibitor ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Conventional Chemotherapy ◽  
Unresectable Tumor ◽  
Braf Fusion

Abstract Background Low grade glioma (LGG) is the most common central nervous system (CNS) tumor in children. Some are treated with surgery alone, while chemotherapy is given for unresectable tumor with clinical symptoms or progression. Conventional chemotherapy is effective but 30–40% patients may have reactivation of disease requiring re-treatment throughout lifetime. MEK inhibitor for BRAF-fusion positive LGG is a new treatment option for refractory cases. Methods Retrospective search in territory-wide pediatric oncology registry for children diagnosed with LGG from 2010–2020 in Hong Kong. To identify patients with molecular confirmed BRAF-fusion positive LGG and any treatment with MEK inhibitor. Results Twelve patients (N=12) were identified with BRAF-fusion positive LGG, male:female was 1:2, age 0.3–15.1yr (median 5.0yr) at presentation. The median follow up duration was 1.8yr. Five patients (42%) had surgical resection only. Seven patients (58%) were given chemotherapy with Carboplatin / Vincristine. Five out of seven (n=7) treated patients (71%) have partial response at their initial treatment. Two patients (29%) had progressive disease during treatment and switched to second-line chemotherapy, vinblastine however without improvement. Three patients required re-treatment as disease reactivation. Total five patients had refractory diseases were treated with MEK inhibitor, Trametinib including one diagnosed NF-1. All of them have adverse skin reaction and raised transaminase with one required dose reduction. They have been taking the MEK inhibitor for 0.1–3.3 yr with sustainable partial response. Conclusion Pediatric LGG has overall favourable prognosis. Some of them treated with surgery alone while conventional chemotherapy could also achieve satisfactory disease control. For refractory disease with BRAF-fusion positive, MEK inhibitor is a well tolerated treatment option showing sustainable partial response. However, prolonged medication and disturbing skin reaction are still a major concern for this group of patients. On-going clinical trials to compare conventional chemotherapy versus MEK inhibitor could give us more insight about the clinical benefit, patient selection and treatment duration.

scholarly journals HGG-06. REMARKABLE RESPONSE TO BRAF INHIBITOR IN AN INFANT WITH DISSEMINATED DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii345-iii345
Author(s):  
Le Le Aung
Keyword(s):  
Braf Inhibitor ◽  
Braf V600e ◽  
Proliferation Index ◽  
Glioneuronal Tumor ◽  
Low Grade ◽  
Braf Inhibitors ◽  
Visual Contact ◽  
Ki 67 ◽  
Low Grade Gliomas ◽  
Diffuse Leptomeningeal Glioneuronal Tumor

Abstract INTRODUCTION Diffuse Leptomeningeal Glioneuronal Tumor (DLGNT) are rare CNS tumors and in infants, they can be lethal. There are several anecdotal reports in infants with low grade gliomas (LGG) with treated with BRAF inhibitors. METHODS A six-month old baby girl presented with a 2-week history of absent visual contact and vomiting. Imaging revealed a large 4.7 X 4.2 X 2.8 cm suprasellar charismatic region mass and multiple small extra-axial plaques in spinal canal. The child developed significant ascites post VP shunt requiring shunt externalization, extensive protein infusion support and hospitalization for six weeks. Immunohisto-chemical staining revealed Olig-2 and S-100, GFAP and synaptophysin positive. EMA showed patchy cytroplasmic reactivity in stromal cells and CD99 showed diffuse reactivity in stromal and lesional cells. INI-1, IDH-1, and CD117 were negative. Ki-67 proliferation index was 8–10%. PCR for BRAF V600E/E2/D was detected and KIAA1549-BRAF fusion as negative. This was confirmed by Genome Wide Next Generation Sequencing. While waiting for GNS testing results, the baby received one dose of Vinblastine. However, within seven days of initiating Debrafenib, significant clinical and radiological responses were observed. CONCLUSION The baby continues safely on Debrafenib with continued dramatic radiological response. This suggest that there may be a role in early initiation of targeted therapy such as BRAF inhibitors rather than giving standard chemotherapy such as Vinblastine or Carboplatin-Vincristine in extremely ill infants with low grade gliomas.

scholarly journals PATH-44. AN UNUSUAL PRESENTATION OF A PEDIATRIC MIDLINE H3K27M-MUTANT TUMOR WITH DISSEMINATED CRANIOSPINAL LEPTOMENINGEAL DISEASE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii174-ii174
Author(s):  
Ralph Navarro ◽  
Danielle Golub ◽  
Travis Hill ◽  
Michelle McQuinn ◽  
Nora Kim ◽  
...  
Keyword(s):  
Treatment Response ◽  
Molecular Signature ◽  
Proliferation Index ◽  
Glioneuronal Tumor ◽  
Leptomeningeal Disease ◽  
Extensive Literature ◽  
Thalamic Lesion ◽  
Leptomeningeal Spread ◽  
Local Progression ◽  
Diffuse Leptomeningeal Glioneuronal Tumor

Abstract BACKGROUND H3K27M-mutant midline lesions were recently reclassified by the WHO as “Diffuse Midline Glioma” (DMG) based on their molecular signature. DMG is one of the most common and most lethal pediatric brain tumors; terminal progression is typically caused by local progression or secondary leptomeningeal dissemination. H3K27M mutations have also been infrequently associated with a histologically diverse set of lesions, particularly spinal masses with early leptomeningeal spread, but the role of H3K27M in these atypical lesions remains poorly understood. CASE PRESENTATION A 15-year-old girl was found to have a T2/FLAIR-hyperintense and heterogeneously contrast-enhancing thalamic mass accompanied by severe leptomeningeal enhancement along the entire neuraxis. Initial infectious workup was negative, and open intracranial biopsy was inconclusive. Follow-up spinal arachnoid biopsy was diagnostic for H3K27M neuroepithelial tumor, thereafter classified as DMG. Biopsy also showed focal p53 immunopositivity, variable immunoreactivity for GFAP and synaptophysin, and an increased proliferation index, altogether suggestive of a glioneuronal origin. She received craniospinal irradiation (CSI) to 41.4Gy with a boost to the thalamic lesion to 54Gy. Imaging 1-month post-radiation demonstrated significant treatment response only with residual enhancement at the conus. CONCLUSIONS This case report describes the unique presentation of an H3K27M-mutant midline lesion with significant craniospinal leptomeningeal spread on admission and atypical glioneuronal histopathological markers. Given her avid leptomeningeal disease, spinal dural biopsy could have been considered earlier given its diagnostic yield in classifying the lesion as DMG. This lesion, however, additionally demonstrated synaptophysin positivity. Per extensive literature review, this histopathology is also potentially consistent with diffuse leptomeningeal glioneuronal tumor (DLGNT). This patient’s uniquely marked treatment response to CSI is also not typically observed in DMG, further supporting the possibility of an alternative molecular identity. In atypical DMG cases, particularly with early leptomeningeal spread, additional consideration of clinical and histopathological context is warranted for accurate diagnosis and prognostication.

Anaplastic Glioneuronal Tumor With KIAA1549/BRAF Fusion

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S102-S102
Author(s):  
Zhenggang Xiong ◽  
Prithvi Narayan
Keyword(s):  
Neoplastic Cell ◽  
Glioneuronal Tumor ◽  
Low Grade ◽  
High Grade ◽  
Left Frontal Lobe ◽  
Ki 67 ◽  
Blurry Vision ◽  
Immunohistochemical Assessment ◽  
Braf Fusion ◽  
Glioneuronal Tumors

Abstract Introduction Glioneuronal tumors are usually low grade and have a favorable prognosis. The anaplastic glioneuronal tumor with KIAA1549/BRAF fusion has not yet been documented. This article reports a pediatric case of glioneuronal tumor with anaplasia and KIAA1549/BRAF fusion to illuminate the importance of KIAA1549/BRAF fusion in the tumorigenesis and clinical management of high-grade glioneuronal tumors. Case Presentation A 10-year-old boy presented with 1 year of headache and 3 months of blurry vision and proptosis. Ophthalmologic evaluation revealed bilateral papilledema. Magnetic resonance imaging showed a large mixed cystic and solid mass in the left frontal lobe of cerebrum. Histologic analysis demonstrated a glioneuronal tumor with papillary/pseudopapillary growth pattern, focal necrosis, microcalcification, and brisk mitotic activity with a high Ki-67 labeling index of focally up to 20%. Immunohistochemical assessment identified a mixed glial and neuronal neoplastic cell population. Molecular studies revealed a KIAA1549/BRAF fusion. Conclusion KIAA1549/BRAF fusion may play an important role in the oncogenesis of high-grade glioneuronal tumors. In view of the fact that effective, targeted therapies for the tumors with KIAA1549/BRAF fusion are clinically available, detection of KIAA1549/BRAF fusion for glioneuronal tumors, particularly high-grade glioneuronal tumors, is helpful.

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