scholarly journals LGG-48. PROLIFIC GROWTH OF BRAF V600E MUTANT PILOCYTIC ASTROCYTOMA WHILE ON KETOGENIC DIET: CASE REPORT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii375-iii375
Author(s):  
Patti Batchelder ◽  
Anandani Nellan ◽  
Charuta Joshi ◽  
Adam Green ◽  
Michael Handler ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Ketogenic Diet ◽  
Pilocytic Astrocytoma ◽  
Intractable Epilepsy ◽  
Braf V600e ◽  
Tumor Control ◽  
Low Grade ◽  
Brafv600e Mutation ◽  
Human Patient ◽  
Common Diagnosis

Abstract Epilepsy is a common diagnosis among pediatric patients with supratentorial tumors, particularly infiltrating gliomas. The ketogenic diet can be a successful antiepileptic therapy for patients with medically intractable epilepsy. Acetoacetate, a main ketone released during ketosis, has been shown to increase BRAFV600E binding to MEK1 and MEK1 phosphorylation in BRAFV600E mutant melanoma cells, thereby promoting proliferation and tumor growth (Kang et al, 2015, Xia et al, 2017). BRAFV600E mutation is common in pediatric low-grade gliomas. Therefore, use of a ketogenic diet to manage coincident epilepsy could, in theory, promote tumor growth. However, this has not been previously reported in a human patient. We present a 3 year-old male with a non-NF1 optic pathway BRAFV600E mutant pilocytic astrocytoma and medically intractable epilepsy. He was treated with carboplatin and bevacizumab for 1 year, with good tumor response and vision recovery. He showed stable, non-progressive disease for several months. He was placed on a ketogenic diet 9 months into treatment and became seizure free. Tumor recurrence occurred at 8 months off therapy, at which time a biopsy demonstrated BRAFV600E mutation. The tumor progressed rapidly despite treatment with Trametinib and Dabrafenib, leading to salvage therapy with carboplatin, vinblastine, bevacizumab, and XRT, without tumor control. We discuss the potential effect of the ketogenic diet on this patient’s outcome.

scholarly journals LGG-23. EXCELLENT CLINICAL / RADIOLOGICAL RESPONSE TO BRAF INHIBITION IN A YOUNG CHILD WITH IN-OPERABLE SUPRA-SELLAR PILOCYTIC ASTROCYTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii370-iii371
Author(s):  
Stacy Chapman ◽  
Demitre Serletis ◽  
Colin Kazina ◽  
Mubeen Rafay ◽  
Sherry Krawitz ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Pilocytic Astrocytoma ◽  
Clinical Symptoms ◽  
Obstructive Hydrocephalus ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Low Grade ◽  
Dramatic Improvement ◽  
Chemotherapeutic Regimen ◽  
Response To Chemotherapy

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.

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.

scholarly journals RARE-32. POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG (PLNTY): GENETIC ANALYSIS CONFIRMS FREQUENT MAPK PATHWAY ACTIVATION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi228-vi228
Author(s):  
Cristiane Ida ◽  
Derek Johnson ◽  
Thomas Kollmeyer ◽  
DongKun Kim ◽  
Timothy Kaufmann ◽  
...  
Keyword(s):  
Pilocytic Astrocytoma ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Chromosome 17 ◽  
Chromosomal Microarray ◽  
Low Grade ◽  
Fusion Event ◽  
Dna And Rna ◽  
Pathway Activation

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and genetic MAPK pathway activation through alterations such as BRAF V600E mutation, and FGFR2-KIAA1598/CTNNA3 and FGFR3-TACC3 fusions. We report the molecular profiling of PLNTY in 9 patients, 7 female: 2 male, median age at diagnosis of 16 years (range, 5–34). All tumors were supratentorial with diagnostic morphological features of PLNTY including oligodendroglioma-like areas and strong diffuse CD34 immunostaining. Four (of 9; 44%) tumors were positive for BRAF V600E immunostain, indicating the presence of a BRAF V600E mutation. The 6 cases evaluated for IDH status were negative by IDH1-R132H immunostain (n=5; 3 BRAF V600E-negative and 2 BRAF V600E-positive) or by NGS (n=1; BRAF V600E-negative). Oncoscan chromosomal microarray performed in 5 BRAF V600E-negative tumors showed recurrent copy number changes including gain of whole chromosomes 5, 7, 8, 9, 12, 18, 19, 20, 21 and X, and loss of chromosomes 1, 2, 10q, 13, 22 and Xq. The 10q losses (n=2) were highly suggestive of an FGFR2-KIAA1598 and of a potentially novel FGFR2 underlying fusion event in one case each. Custom targeted neuro-oncology DNA and RNA NGS panel performed in 2 cases revealed a fusion similar to fusions previously reported in pilocytic astrocytoma: one with a KIAA1549-BRAF (exon 15-exon 9) fusion associated with a 7q34 ~785 kilobase deletion rather than the characteristic ~2 megabase duplication seen in pilocytic astrocytoma, and another with a QKI-NTRK2 (exon 6-exon 15) fusion associated with a 9q21 ~191 kilobase duplication disrupting NTRK2. The KIAA1549-BRAF fusion-positive case also had a TP53 mutation with loss of whole chromosome 17, suggesting TP53 complete inactivation. This study confirms that PLNTY is a low-grade neuroepithelial tumor with frequent MAPK pathway activation and expands the spectrum of MAPK activating alterations observed in PLNTY.

Pediatric ganglioglioma of the brainstem and cervicomedullary junction: a retrospective cohort study

2020 ◽  
Vol 25 (1) ◽  
pp. 30-36
Author(s):  
Soliman Oushy ◽  
Avital Perry ◽  
Christopher S. Graffeo ◽  
Aditya Raghunathan ◽  
Lucas P. Carlstrom ◽  
...  
Keyword(s):  
Tertiary Care ◽  
Significant Risk ◽  
Foot Drop ◽  
Cranial Neuropathy ◽  
Primary Study ◽  
Tumor Control ◽  
Subtotal Resection ◽  
Low Grade ◽  
Surgical Morbidity ◽  
Cervicomedullary Junction

OBJECTIVEGanglioglioma is a low-grade central nervous system neoplasm with a pediatric predominance, accounting for 10% of all brain tumors in children. Gangliogliomas of the cervicomedullary junction (GGCMJs) and brainstem (GGBSs) present a host of management challenges, including a significant risk of surgical morbidity. At present, understanding of the prognostic factors—including BRAF V600E status—is incomplete. Here, the authors report a single-institution GGCMJ and GGBS experience and review the pertinent literature.METHODSA prospectively maintained neurosurgical database at a large tertiary care academic referral center was retrospectively queried for cases of GGCMJ pathologically confirmed in the period from 1995 to 2015; appropriate cases were defined by diagnosis codes and keywords. Secondary supplemental chart review was conducted to confirm or capture relevant data. The primary study outcome was treatment failure as defined by evidence of radiographic recurrence or progression and/or clinical or functional decline. A review of the literature was conducted as well.RESULTSFive neurosurgically managed GGBS patients were identified, and the neoplasms in 4 were classified as GGCMJ. All 5 patients were younger than 18 years old (median 15 years, range 4–16 years) and 3 (60%) were female. One patient underwent gross-total resection, 2 underwent aggressive subtotal resection (STR), and 2 underwent stereotactic biopsy only. All patients who had undergone STR or biopsy required repeat resection for tumor control or progression. Progressive disease was treated with radiotherapy in 2 patients, chemotherapy in 2, and chemoradiotherapy alone in 1. Immunostaining for BRAF V600E was positive in 3 patients (60%). All 5 patients experienced at least one major complication, including wound infection, foot drop, hemiparesis, quadriparesis, cranial neuropathy, C2–3 subluxation, syringomyelia, hydrocephalus, aspiration, and coma. Overall mortality was 20%, with 1 death observed over 11 years of follow-up.CONCLUSIONSGGBS and GGCMJ are rare, benign posterior fossa tumors that carry significant perioperative morbidity. Contemporary management strategies are heterogeneous and include combinations of resection, radiotherapy, and chemotherapy. The BRAF V600E mutation is frequently observed in GGBS and GGCMJ and appears to have both prognostic and therapeutic significance with targeted biological agents.

Combination of microsurgery and Gamma Knife surgery for the treatment of intracranial chondrosarcomas

2006 ◽  
Vol 105 (Supplement) ◽  
pp. 18-25 ◽  
Author(s):  
Petter Förander ◽  
Tiit Rähn ◽  
Lars Kihlström ◽  
Elfar Ulfarsson ◽  
Tiit Mathiesen
Keyword(s):  
Gamma Knife ◽  
Cranial Nerve ◽  
Residual Tumor ◽  
Local Tumor Control ◽  
Gamma Knife Surgery ◽  
Long Term Results ◽  
Tumor Control ◽  
Low Grade ◽  
Cranial Nerve Palsies ◽  
Tumor Volume Reduction

ObjectIntracranial chondrosarcomas have a high risk of recurrence after surgery. This retrospective study of patients with intracranial chondrosarcoma was conducted to determine the long-term results of microsurgery followed by Gamma Knife surgery (GKS) for residual tumor or recurrence.MethodsThe authors treated nine patients whose median age was 36 years. Seven patients had low-grade chondrosarcomas (LGCSs), whereas mesenchymal chondrosarcomas (MCSs) were diagnosed in two. Radiosurgery was performed in eight patients, whereas one patient declined further surgical intervention and tumor-volume reduction necessary for the GKS.The patients were followed up for 15 to 173 months (median 108 months) after diagnosis and 3 to 166 months (median 88 months) after GKS. Seven patients had residual tumor tissue after microsurgery, and two operations appeared radical. In the two latter cases, tumors recurred after 25 and 45 months. Thus, definite tumor control was not achieved after surgery alone in any patient, whereas the addition of radiosurgery allowed tumor control in all six patients with LGCSs. Two of these patients experienced an initial tumor regrowth after GKS; in both cases the recurrences were outside the prescribed radiation field. The patients underwent repeated GKS, and subsequent tumor control was observed. An MCS was diagnosed in the remaining two patients. Complications after microsurgery included diplopia, facial numbness, and paresis. After GKS, one patient had radiation necrosis, which required microsurgery, and two patients had new cranial nerve palsies.Conclusions Tumor control after microsurgery alone was not achieved in any patient, whereas adjuvant radiosurgery provided local tumor control in six of eight GKS-treated patients. Tumor control was not achieved in the two patients with MCS. Similar to other treatments for intracranial chondrosarcoma, morbidity after micro- and radiosurgical combination therapy was high and included severe cranial nerve palsies.

BRAFV600E MUTATION IN PAPILLARY THYROID CARCINOMA. CLINICAL AND METHODOLOGICAL ASPECTS

2019 ◽  
Vol 65 (1) ◽  
pp. 16-26
Author(s):  
Pavel Rumyantsev ◽  
Petr Nikiforovich ◽  
Andrey Poloznikov ◽  
Andrey Abrosimov ◽  
Vladimir Saenko ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Kinase Inhibitors ◽  
Anaplastic Carcinoma ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Brafv600e Mutation ◽  
Wide Range ◽  
Methodological Aspects

Mutation BRAFV600E is highly specific for papillary thyroid carcinoma. It’s detected in 40-70% of all papillary thyroid carcinoma cases. Moreover this mutation is noticed in anaplastic carcinoma in 40-50%.This fact gives a chance to select patients and provide targeted therapy with multi-kinase inhibitors in cases of unresectable anaplastic carcinoma. The influence of BRAF V600E mutation for response to radioactive iodine therapy requires more evidence-based research. Existing methods for determining the BRAFV600E mutation have different accuracy, availability and cost. Other methodological aspects are also associated with the sample preparation of biological material, the quality of reagents, and the cross-validation of research results. In this review, on the basis of our own experience and literature data, the indications for determining the mutation of the BRAFV600E gene in clinical practice are refined, and a comprehensive comparative analysis of modern research methods has been conducted. This review is focused on a wide range of specialists of different types: oncologists, endocrinologists, radiologists, pathologists, and biologists.

scholarly journals Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stefanie Schwinn ◽  
Zeinab Mokhtari ◽  
Sina Thusek ◽  
Theresa Schneider ◽  
Anna-Leena Sirén ◽  
...  
Keyword(s):  
Fluorescence Microscopy ◽  
Tumor Growth ◽  
Intensive Therapy ◽  
Xenograft Model ◽  
Light Sheet ◽  
Tumor Control ◽  
Orthotopic Model ◽  
Group 3 ◽  
Light Sheet Fluorescence Microscopy

AbstractMedulloblastoma is the most common high-grade brain tumor in childhood. Medulloblastomas with c-myc amplification, classified as group 3, are the most aggressive among the four disease subtypes resulting in a 5-year overall survival of just above 50%. Despite current intensive therapy regimens, patients suffering from group 3 medulloblastoma urgently require new therapeutic options. Using a recently established c-myc amplified human medulloblastoma cell line, we performed an in-vitro-drug screen with single and combinatorial drugs that are either already clinically approved or agents in the advanced stage of clinical development. Candidate drugs were identified in vitro and then evaluated in vivo. Tumor growth was closely monitored by BLI. Vessel development was assessed by 3D light-sheet-fluorescence-microscopy. We identified the combination of gemcitabine and axitinib to be highly cytotoxic, requiring only low picomolar concentrations when used in combination. In the orthotopic model, gemcitabine and axitinib showed efficacy in terms of tumor control and survival. In both models, gemcitabine and axitinib were better tolerated than the standard regimen comprising of cisplatin and etoposide phosphate. 3D light-sheet-fluorescence-microscopy of intact tumors revealed thinning and rarefication of tumor vessels, providing one explanation for reduced tumor growth. Thus, the combination of the two drugs gemcitabine and axitinib has favorable effects on preventing tumor progression in an orthotopic group 3 medulloblastoma xenograft model while exhibiting a favorable toxicity profile. The combination merits further exploration as a new approach to treat high-risk group 3 medulloblastoma.

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.

scholarly journals LGG-30. TRAMETINIB-ASSOCIATED HYPONATREMIA IN A CHILD WITH LOW GRADE GLIOMA IS NOT SEEN FOLLOWING TREATMENT WITH ALTERNATIVE MEK INHIBITOR

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii372-iii372
Author(s):  
Margot A Lazow ◽  
Sarah A Lawson ◽  
Ralph Salloum ◽  
Trent R Hummel ◽  
Natasha Pillay Smiley ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Fluid Intake ◽  
Single Agent ◽  
Mek Inhibitor ◽  
Tumor Control ◽  
Low Grade ◽  
Pituitary Dysfunction ◽  
Adequate Understanding ◽  
Pediatric Patient Population ◽  
Inhibitor Combination

Abstract Molecularly targeted therapy with MEK inhibitors is increasingly being incorporated into the treatment of pediatric low-grade gliomas (LGGs). Trametinib is an orally available MEK1/2 inhibitor that has demonstrated tumor control in LGGs with BRAF alterations. Safe expansion of MEK inhibitor therapy within the pediatric patient population demands adequate understanding of and surveillance for potential MEK-inhibitor specific toxicities, especially among young children. Hyponatremia has been reported in adult patients receiving BRAF/MEK inhibitor combination treatment as well as in two pediatric patients with known diabetes insipidus treated with trametinib monotherapy. To our knowledge, single-agent trametinib has not previously been reported to be associated with hyponatremia in children in the absence of an underlying endocrinopathy. We present a case of hyponatremia associated with trametinib use in an infant with progressive LGG without known endocrine dysfunction, which recurred after significant dose reduction. Therapy with an alternative MEK1/2 inhibitor, binimetinib, provided excellent tumor response without hyponatremia. Hyponatremia is a rare but serious side effect of trametinib, even without underlying pituitary dysfunction. Infants and patients lacking the ability to quickly regulate fluid intake in response to osmolality changes are at particular risk of suffering severe consequences from hyponatremia and should be monitored closely with initiation of trametinib. Switching to a different drug within the same class may offer an alternative to significant dose reduction or discontinuation due to this toxicity.

Sign in / Sign up

Export Citation Format

Share Document