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 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.

scholarly journals LGG-59. REMARKABLE OBJECTIVE RESPONSE AND FAVORABLE SURVIVAL FOR BRAF-V600E CHILDHOOD LOW-GRADE GLIOMAS TO BRAF INHIBITORS COMPARED CONVENTIONAL CHEMOTHERAPY

2018 ◽  
Vol 20 (suppl_2) ◽  
pp. i117-i117
Author(s):  
Michal Zapotocky ◽  
Scott Ryall ◽  
Kohei Fukuoka ◽  
Ana Guerreiro Stucklin ◽  
Julie Bennett ◽  
...  
Keyword(s):  
Objective Response ◽  
Braf V600e ◽  
Low Grade ◽  
Braf Inhibitors ◽  
Conventional Chemotherapy ◽  
Low Grade Gliomas

scholarly journals Low-grade gliomas with the V600E mutation in the BRAF gene in children: clinical features and treatment options

2020 ◽  
Vol 19 (4) ◽  
pp. 58-65
Author(s):  
L. I. Papusha ◽  
E. F. Valiakhmetova ◽  
A. E. Druy ◽  
L. A. Yasko ◽  
K. A. Voronin ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Treatment Options ◽  
Molecular Genetic ◽  
Braf Inhibitor ◽  
Complete Response ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Molecular Characteristics ◽  
Low Grade ◽  
Low Grade Gliomas

The main pathogenetic mechanism of the development of pediatric low grade gliomas (pLGGs) is genetic aberrations in BRAF gene. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. We analyzed the clinical and molecular characteristics of 69 patients with LGGs. Molecular genetic testing for BRAF V600E mutation was performed by allele-specific real-time PCR and Sanger sequencing. BRAF V600E mutation was detected in 15 (21.7%) patients with LGG. The majority of BRAF-mutated cases of LGGs had the midline location: OPG – 7, subcortical ganglia – 1, brainstem – 2. The 2-year PFS was much worse in patients with BRAF V600E compared to patients without this mutation – 30% and 66.2%, respectively. The median time to progression for patients with BRAF V600E mutation was 9.5 months compared to 3.1 years for patients without indicated substitution. 5 patients with BRAF V600E-mutated LGGs who experienced progression after the conventional treatment, received targeted therapy (BRAF-inhibitor-3, BRAF + MEK inhibitors – 2) with good response (complete response – 2, partial response – 3). BRAF V600E mutation contributes to poor outcome in patients with LGGs Targeted therapy could be effective in this cohort of patients.

scholarly journals HGG-02. ADOLESCENT AND YOUNG ADULT (AYA) GLIOMA WITH BRAF V600E-MUTANTATION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii344-iii344
Author(s):  
Yui Kimura ◽  
Yukitomo Ishi ◽  
Yuko Watanabe ◽  
Yoshiko Nakano ◽  
Shigeru Yamaguchi ◽  
...  
Keyword(s):  
Braf Inhibitor ◽  
Clinical Information ◽  
Early Recurrence ◽  
Pleomorphic Xanthoastrocytoma ◽  
Adolescent And Young Adult ◽  
Braf V600e ◽  
Low Grade ◽  
Diffuse Astrocytoma ◽  
Genetic Features ◽  
Epithelioid Glioblastoma

Abstract BACKGROUND Biological features of pediatric glioma differ significantly from those of adult glioma, and limited data are available on those of AYA patients. Here, we focused on AYA patients with glioma, especially those harboring BRAF V600E mutation, and investigated their clinical and genetic features. METHOD: We retrospectively analyzed AYA patients with brain tumors harboring BRAF V600E, who were treated in two hospitals in Japan. RESULTS Clinical information was available for 14 patients. The median age at diagnosis was 25 years (range: 15–38). Five patients were diagnosed with glioblastoma (GBM), including one epithelioid type. These patients were over 25. Although one patient with GBM died of the disease 6.9 years after initial diagnosis, the remaining patients were alive. Two patients were alive without recurrence at 38 and 51 months after the treatment. The patient with epithelioid glioblastoma experienced early recurrence. The remaining nine patients (64%) were diagnosed with low-grade glioma, including ganglioglioma, pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma, pleomorphic xanthoastrocytoma, and polymorphous low-grade neuroepithelial tumor of the young. No patients died of the disease, and four patients are alive without recurrence after initial operation without adjuvant treatment. Two patients are (epithelioid glioblastoma and ganglioglioma) currently undergoing treatment with a BRAF inhibitor for recurrent tumors. DISCUSSION Although the number of this study is limited, our study suggested that the prognosis of AYA patients with BRAF-V600E positive GBM may not be as dismal as that of children or adults.

Molecular Alterations in Pediatric Low-Grade Gliomas That Led to Death

2021 ◽  
Author(s):  
Jared T Ahrendsen ◽  
Claire Sinai ◽  
David M Meredith ◽  
Seth W Malinowski ◽  
Tabitha M Cooney ◽  
...  
Keyword(s):  
Braf V600e ◽  
Molecular Characteristics ◽  
Low Grade ◽  
Diffuse Astrocytoma ◽  
Term Survival ◽  
Pten Loss ◽  
Low Grade Gliomas ◽  
Molecular Alterations ◽  
Idh1 R132h ◽  
Poor Outcomes

Abstract Pediatric low-grade gliomas (PLGGs) have excellent long-term survival, but death can occasionally occur. We reviewed all PLGG-related deaths between 1975 and 2019 at our institution: 48 patients were identified; clinical data and histology were reviewed; targeted exome sequencing was performed on available material. The median age at diagnosis was 5.2 years (0.4–23.4 years), at death was 13.0 years (1.9–43.2 years), and the overall survival was 7.2 years (0.0–33.3 years). Tumors were located throughout CNS, but predominantly in the diencephalon. Diagnoses included low-grade glioma, not otherwise specified (n = 25), pilocytic astrocytoma (n = 15), diffuse astrocytoma (n = 3), ganglioglioma (n = 3), and pilomyxoid astrocytoma (n = 2). Recurrence occurred in 42/48 cases, whereas progression occurred in 10. The cause of death was direct tumor involvement in 31/48 cases. Recurrent drivers included KIAA1549-BRAF (n = 13), BRAF(V600E) (n = 3), NF1 mutation (n = 3), EGFR mutation (n = 3), and FGFR1-TACC1 fusion (n = 2). Single cases were identified with IDH1(R132H), FGFR1(K656E), FGFR1 ITD, FGFR3 gain, PDGFRA amplification, and mismatch repair alteration. CDKN2A/B, CDKN2C, and PTEN loss was recurrent. Patients who received only chemotherapy had worse survival compared with patients who received radiation and chemotherapy. This study demonstrates that PLGG that led to death have diverse molecular characteristics. Location and co-occurring molecular alterations with malignant potential can predict poor outcomes.

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 Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

2017 ◽  
Vol 35 (25) ◽  
pp. 2934-2941 ◽  
Author(s):  
Alvaro Lassaletta ◽  
Michal Zapotocky ◽  
Matthew Mistry ◽  
Vijay Ramaswamy ◽  
Marion Honnorat ◽  
...  
Keyword(s):  
Quantitative Imaging ◽  
Progression Free Survival ◽  
Extent Of Resection ◽  
Braf V600e ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Molecular Stratification ◽  
Treatment Data ◽  
Poor Outcomes ◽  
Independent Cohort

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

scholarly journals Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition

2020 ◽  
pp. 561-571 ◽  
Author(s):  
Liana Nobre ◽  
Michal Zapotocky ◽  
Vijay Ramaswamy ◽  
Scott Ryall ◽  
Julie Bennett ◽  
...  
Keyword(s):  
Objective Response ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Homozygous Deletion ◽  
Braf V600e ◽  
Rapid Progression ◽  
Low Grade ◽  
Term Survival ◽  
Braf Inhibition ◽  
Poor Outcomes

PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02). CONCLUSION Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

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