Multimodiale Therapie von Hirnmetastasen

2020 ◽  
Vol 46 (05) ◽  
pp. 228-231
Author(s):  
M. Ahmed ◽  
F. Meier ◽  
S. Beissert
Keyword(s):  
Zielgerichtete Therapie ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Epileptischer Anfall ◽  
Neurologische Defizite ◽  
Ca 50

ZusammenfassungDas Langzeitüberleben hat sich für Patienten mit metastasiertem Melanom durch die Etablierung der zielgerichteten Therapien sowie Immuntherapien mit 5-Jahres-Überlebensraten von ca. 50 % deutlich verbessert. Hirnmetastasen stellen jedoch weiterhin eine therapeutische Herausforderung dar. In der Vergangenheit lag das mediane Überleben für Patienten mit neu diagnostizierten Hirnmetastasen bei 2 – 6 Monaten 1. Retrospektive Analysen sprechen für einen Überlebensbenefit unter multimodaler Therapie mit einer 5-Jahres-Überlebensrate von über 20 % 1.Wir berichten über einen 50-jährigen Patienten mit multiplen symptomatischen Hirnmetastasen bei Erstdiagnose. Nach Exstirpation einer symptomatischen Metastase wurde bei BRAF-V600E-Mutation eine Systemtherapie mit dem BRAF-Inhibitor Dabrafenib in Kombination mit dem MEK-Inhibitor Trametinib eingeleitet. Hierunter zeigte sich ein rascher deutlicher Regress der zerebralen und extrazerebralen Metastasen. Nach 8 Wochen wurde die Systemtherapie auf eine Immuntherapie mit Nivolumab plus Ipilimumab umgesetzt. Kurz nach Therapieeinleitung trat ein epileptischer Anfall auf und die Hirnmetastasen zeigten sich wieder progredient. Zwei symptomatische Hirnmetastasen wurden reseziert, eine Ganzhirnradiatio mit Hippocampusschonung wurde eingeleitet und die Immuntherapie fortgesetzt. Aktuell erfolgt eine zielgerichtete Therapie mit Encorafenib und Binimetinib. 17 Monate nach Erstdiagnose befindet sich der Patient in gutem Allgemeinzustand ohne neurologische Defizite. Dieser Fallbericht bestätigt den retrospektiv beobachteten Überlebensbenefit für Patienten mit Hirnmetastasen unter multimodaler Therapie.

Treatment of a BRAF V600E Positive Ameloblastoma in a Pediatric Patient with MEK Inhibitor Monotherapy

FACE ◽  
2021 ◽  
pp. 273250162110051
Author(s):  
Steven Daws ◽  
Kongkrit Chaiyasate ◽  
Arshi Lehal
Keyword(s):  
Mapk Pathway ◽  
Case Reports ◽  
Radical Resection ◽  
Mek Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Targeted Chemotherapy ◽  
Odontogenic Epithelium ◽  
Genetic Landscape ◽  
Frequent Presence

Ameloblastomas are uncommon tumors of the odontogenic epithelium standardly treated with radical resection. Recent studies of the genetic landscape of ameloblastoma have revealed the frequent presence of the BRAF V600E mutation, suggesting a possible role for targeted chemotherapy. We present the case of a primary mandibular ameloblastoma found in a 13-year-old female with confirmed BRAF V600E mutation. Prior to invasive surgical intervention she was treated for 8 weeks with the MEK inhibitor trametinib, but her tumor demonstrated little radiographic, clinical, or histologic response. Previous case reports have shown ameloblastoma in adult patients to be responsive to other agents targeting the MAPK pathway. Our observations in the presented case demonstrate the need for further research into the utility of targeted chemotherapy in ameloblastoma treatment.

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.

Anaplastic Thyroid Cancer

2019 ◽  
Author(s):  
Geeta Lal
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Braf Inhibitor ◽  
Anaplastic Thyroid Cancer ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Multidisciplinary Teams ◽  
Neoadjuvant Radiotherapy ◽  
Current State ◽  
Targeted Treatments

Anaplastic thyroid cancer (ATC) is a rare thyroid malignancy with a nearly uniform poor prognosis. Most patients present with advanced disease, and optimal management requires rapid diagnosis, staging, and involvement of multidisciplinary teams. Treatment may include surgery in patients with resectable disease and adjuvant or neoadjuvant radiotherapy and chemotherapy. Improved understanding of molecular pathogenesis has allowed the assessment of tyrosine kinase inhibitors and other targeted treatments in these patients.  The FDA recently approved the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAF V600E mutation positive, unresectable or metastatic ATC. This review summarizes the current state-of-the-art concepts in the management of patients with ATC. This review contains 3 figures, 2 tables, and 25 references. Key words: anaplastic thyroid cancer, goals of care discussion, management, surgery, radiotherapy, chemotherapy novel therapies, NCCN and ATA guidelines

scholarly journals Salutary Response to Targeted Therapy in Anaplastic Thyroid Cancer

2019 ◽  
Vol 7 ◽  
pp. 232470961989094 ◽  
Author(s):  
Sasan Fazeli ◽  
Edina Paal ◽  
Jessica H. Maxwell ◽  
Kenneth D. Burman ◽  
Eric S. Nylen ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Side Effects ◽  
Combination Therapy ◽  
Braf Inhibitor ◽  
Anaplastic Thyroid Cancer ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Aggressive Tumor ◽  
Well Differentiated

Context. Anaplastic thyroid cancer (ATC) is an aggressive tumor with a median survival of 3 to 9 months, a 1-year survival of less than 10% and without definitive therapies. Recently, in BRAF V600E mutated ATCs, new targeted therapy using a combination of a BRAF inhibitor, dabrafenib (Dab), with a mitogen-activated extracellular protein kinase (MEK) inhibitor, trametinib (Tram), has shown significant promise. Case Description. We report a case of aggressive ATC with 5 sequence mutations: BRAF V600E (mutation fraction [MF] 34%), TERT E441del (MF 37%), RET N579K (MF 55%), EZH2 D154E (MF 60%), and CDK4 S259L (MF 48%). The patient had a dramatic response to the Dab/Tram combination with near complete resolution of his lung, bone, hepatic, and splenic lesions soon after starting therapy. Unfortunately, intolerable side effects (grade 2-3) on this regimen required tapering and discontinuation of the treatment. He had a quick resurgence of disease after stopping the combination therapy. The patient died approximately 3 months after discontinuing Dab/Tram. Autopsy revealed an atrophic thyroid gland with microscopic subcapsular focus of well-differentiated papillary thyroid carcinoma. There was extensive lymphatic spread of the tumor throughout bilateral lungs with fibrosis. No other metastatic site was identified. Conclusion. We report a unique case of ATC with 2 new mutations of EZH2 D154E and CDK S529L. This case exemplifies the significant promise Dab/Tram therapy holds, the potential side effects that limit their use, and autopsy findings status post use of this combination therapy.

scholarly journals The BRAF V600E Mutation Detection by quasa Sensitive Real-Time PCR Assay in Northeast Romania Melanoma Patients

2021 ◽  
Vol 11 (20) ◽  
pp. 9511
Author(s):  
Elena Porumb-Andrese ◽  
Ramona Gabriela Ursu ◽  
Iuliu Ivanov ◽  
Irina-Draga Caruntu ◽  
Vlad Porumb ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Target Therapy ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Clinical Samples ◽  
Primary Cutaneous Melanoma ◽  
Purification Method ◽  
Detection Of Mutations ◽  
National Reporting System

Background: The prevalence of melanoma in Romanian patients is underestimated. There is a need to identify the BRAF V600E mutation to accurately treat patients with the newest approved BRAF inhibitor therapy. This is a pilot study in which we first aimed to choose the optimal DNA purification method from formalin fixation and paraffin embedding (FFPE) malignant melanoma skin samples to assess the BRAF mutation prevalence and correlate it with clinical pathological parameters. Methods: 30 FFPE samples were purified in parallel with two DNA extraction kits, a manual and a semi-automated kit. The extracted DNA in pure and optimum quantity was tested for the BRAF V600E mutation using the quantitative allele-specific amplification (quasa) method. quasa is a method for the sensitive detection of mutations that may be present in clinical samples at low levels. Results: The BRAF V600E mutation was detected in 60% (18/30) samples in patients with primary cutaneous melanoma of the skin. BRAFV600E mutation was equally distributed by gender and was associated with age >60, nodular melanoma, and trunk localization. Conclusions: The high prevalence of BRAF V600E mutations in our study group raises awareness for improvements to the national reporting system and initiation of the target therapy for patients with malignant melanoma of the skin.

scholarly journals Analysis of BRAF and NRAS mutation status in advanced melanoma patients treated with anti-CTLA-4 antibodies: Association with overall survival?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9025-9025 ◽  
Author(s):  
Joanna Mangana ◽  
Simone M. Goldinger ◽  
Katja Schindler ◽  
Sima Rozati ◽  
Anna L. Frauchiger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Advanced Melanoma ◽  
Braf V600e ◽  
Wild Type ◽  
Nras Mutation ◽  
Mutation Status ◽  
Mutational Status ◽  
Melanoma Patients

9025 Background: Ipilimumab and tremelimumab are human monoclonal antibodies against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival with durable-long-term responses for advanced melanoma patients both in first-and second-line setting. Up to date, there is no proven association between the BRAF-V600E mutation and the disease control rate (DCR) in response to Ipilimumab. Moreover, significantly shorter survival rates have been reported in patients harboring an NRAS mutation than in those without. This retrospective analysis was carried out to assess if BRAF (V600) and NRAS mutation status affects the clinical outcome of Ipilimumab-treated melanoma patients. Methods: This is a retrospective multi-center analysisof 71 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The cut-off for the estimation of overall survival was end of November 2012. Results: The median overall survival of BRAFV600/NRAS mutant patients (n=44) was 1,41 years compared with 2.67 years in BRAF/NRAS wild-type patients (n=27). Although this difference was not statistically significant there was a trend for improved survival in wild-type patients. Of the 71 patients analyzed, 56 received chemotherapy prior to Ipilimumab. In the BRAF/NRAS mutant cohort, 12 patients received Ipilimumab following either a BRAF- or a MEK- inhibitor. Of those 12 patients, 8 progressed and were unable to complete Ipilimumab. Of the 4 patients who completed 4 cycles of Ipilimumab, 2 were subsequently treated with a BRAF inhibitor. Furthermore out of the 71 patients, 8 patients received a BRAF or a MEK inhibitor after progression; 5 of them are still alive. Conclusions: This is the first retrospective study to evaluate the association of both BRAF and NRAS mutational status with the overall survival of Ipilimumab-treated patients. There was a trend towards an improved survival in the BRAF/NRAS wild-type subpopulation. Additional patients will be examined to foster these preliminary results.

scholarly journals Low-Dose BRAF-Inhibitors in the Treatment of Histiocytic Disorders with the BRAF-V600E Mutation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5895-5895
Author(s):  
Gordon Ruan ◽  
Gaurav Goyal ◽  
Jithma P. Abeykoon ◽  
N. Nora Bennani ◽  
Karen Rech ◽  
...  
Keyword(s):  
Median Time ◽  
Low Dose ◽  
Braf Inhibitor ◽  
Brain Parenchyma ◽  
Advisory Board ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Starting Dose ◽  
Dose Reductions

Introduction: The landmark VE-BASKET trial demonstrated that Erdheim-Chester disease (ECD) patients with the BRAF-V600E mutation can be effectively treated with vemurafenib 1920 mg/day. However, all patients required dose reductions due to adverse effects. The efficacy of low dose BRAF-inhibitors is not well established in ECD. Further, as Langerhans cell histiocytosis (LCH) also harbors BRAF-V600E mutations in 50-60% of patients, BRAF-inhibitors may be effective in this disease as well. In this study, we evaluated the efficacy of low dose BRAF-inhibitors (vemurafenib and dabrafenib) in the treatment of ECD and LCH. Methods: We conducted a retrospective study of ECD and LCH patients who were seen at our institution from January 1998 to July 2018. All patients had a diagnosis of ECD and LCH determined by clinical criteria in conjunction with histopathologic findings. Based on the standard doses approved for malignant melanoma and ECD, patients were categorized into the low dose BRAF-inhibitor group if they were treated with vemurafenib < 960 mg/day or dabrafenib ≤ 150mg/day at any point in time. We used a simple response criteria that defined clinical progressive disease (PD) as worsening of symptoms attributed to ECD/LCH or radiologic PD as a progression or worsening of proven or suspected lesions due to ECD/LCH. The minimum duration for symptom improvement to be considered a response was set at 3 months. Results: A total of 89 ECD patients and 186 LCH patients were identified. Within the ECD cohort, 24 of 44 (55%) patients who were tested had the BRAF-V600E mutation. Eight patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis was 57 years (range 37-74) and 5 (63%) were male. The most common areas of involvement included bone (88%), cardiovascular system (63%), kidneys (63%), and brain parenchyma (50%). The median time of follow up was 66 months (range 23-165) and the median time on low-dose BRAF-inhibitor was 10 months (range 1-27) [Table 1]. Three patients had a starting dose of vemurafenib 1920 mg/day, 4 had 960 mg/day, and 1 had 480 mg/day. All patients required dose reductions and 50% of the patients ultimately discontinued vemurafenib due to side effects. Side effects included fatigue, pruritus, nausea, facial swelling, blisters, papillomas, and/or subcutaneous nodules. Four patients were able to remain on low-dose vemurafenib for a median follow up time of 24.5 months (range 12-28) with ongoing response and no signs of clinical or radiologic PD. Within the LCH cohort, 18 of 31 tested (58%) patients had the BRAF-V600E mutation. Four patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis of this cohort was 43 years (range 34-69) and 2 (50%) were male. Areas of involvement included bone (100%), brain parenchyma (hypothalamus/optic stalk and pons; 50%), and skin (25%). The median time of follow up was 31 months (range 21-46) and the median time on low-dose BRAF-inhibitor was 4 months (range 3-24) [Table 2]. Two patients had a starting dose of vemurafenib 960mg/day. The patients with brain parenchymal involvement had a starting dose of dabrafenib 150mg/day or 100mg/day. All patients taking vemurafenib 960mg/day required dose reductions and one patient discontinued treatment due to skin blistering in her feet. In the patients taking dabrafenib, no side effects have yet been reported. 3 patients had an ongoing response and did not have clinical or radiologic PD. Patient #10 however, had clinical and radiologic PD after being on vemurafenib 720mg/day for 22 months. Conclusion: Our study suggests a potential role for lower doses of BRAF-inhibitors in ECD and LCH patients harboring BRAF-V600E mutations. Dabrafenib was found to be particularly efficacious and well-tolerated in LCH involving the brain parenchyma. However, patients who undergo dose reductions should be closely monitored due to the risk of disease progression. Careful balance of toxicities and efficacy is needed for optimizing patient outcomes with targeted therapies. Disclosures Bennani: Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board. OffLabel Disclosure: Vemurafenib and dabrafenib for Langerhans cell histiocytosis. Vemurafenib dosage for Erdheim-Chester disease is less than the approved dose of 960mg every 12 hours.

Relevance of MIA and S-100 to monitor BRAF inhibitor (iBRAF) therapy in metastatic melanoma patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9074-9074
Author(s):  
Miguel F. Sanmamed ◽  
Sara Fernandez-Landazuri ◽  
Eduardo Castanon ◽  
Jose Echeveste ◽  
Maria D. Lozano ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Tumor Markers ◽  
Direct Sequencing ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Best Response ◽  
Response Table ◽  
S 100 ◽  
Melanoma Patients

9074 Background: MIA and S-100 have been proposed as tumor markers for patients with melanoma, but they are not widely accepted. BRAF V600E mutation has been reported in more than 50% of melanomas. Recently, selective BRAF inhibitors have proved to be more active than DTIC in first line treatment of BRAF V600E melanoma patients. The aim of the present work is to evaluate the utility of MIA and S-100 during iBRAF treatment. Methods: BRAF V600E mutation was analyzed in 77 patients with metastatic melanoma by automated direct sequencing in tumor DNA. Tumor markers (MIA, S-100 and LDH) were studied in serum from all patients. Sixteen of these patients received iBRAF therapy (11 Vemurafenib, 5 Dabrafenib) and tumor markers were analyzed sequentially: baseline, best response and progression. MIA and S-100 were determined by immunometric methods and LDH by a spectrophotometric assay. The cut-off points were MIA=9 ug/L, S-100=0.1 ug/L, and LDH=290 U/L. Non-parametric statistical analysis was performed. Results: Forty-three patients had BRAF V600E mutation and 34 were wild type (WT). The percentage of cases with MIA above the cut-off in patients with V600E mutation was significantly higher than in the WT group (76.3% vs. 52.9%; p<0.05), while the frequency of elevated S-100 and LDH was similar. Among patients treated with iBRAF, the response rate was 87.5% (5 CR, 9PR). In responding patients, MIA and S100 levels decreased dramatically, but not LDH (Table). At the time of this report, thirteen patients have progressed. Upon progression, MIA and S-100 increased significantly above levels achieved at best response (Table). Conclusions: Serum MIA and S-100 are potentially useful markers in the clinical and follow-up management of patients receiving iBRAF therapy. Validation in a larger series is needed. [Table: see text]

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