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https://www.readbyqxmd.com/read/28723725/meningeal-melanomatosis-following-discontinuation-of-dabrafenib-implications-for-the-maintenance-of-long-term-complete-remission
#1
Victoria Grätz, Nadine Lüttmann, Ozan Haase, Ewan A Langan, André Kemmling, Detlef Zillikens, Patrick Terheyden
A subset of 10-20% of patients under continuous BRAF inhibitor monotherapy achieve long-term progression-free and overall survival. Definitive criteria for the safe cessation of BRAF inhibitor monotherapy in treatment-responsive melanoma patients are lacking. We report a patient who remained in complete remission (CR) for 5 years under dabrafenib. The treatment was withdrawn because of concerns about cardiac toxicity. Four months thereafter the patient developed neurological symptoms, including diplopia and bilateral visual loss...
July 18, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28720543/involvement-of-the-bh3-only-pro-apoptotic-bik-nbk-in-braf-mek-inhibitor-induced-apoptosis-in-melanoma-cell-lines
#2
Andreas Borst, Sebastian Haferkamp, Johannes Grimm, Manuel Rösch, Guannan Zhu, Sen Guo, Chunying Li, Tianwen Gao, Svenja Meierjohann, David Schrama, Roland Houben
In patients with BRAF-mutated melanoma specific inhibitors of BRAF(V600E) and MEK1/2 frequently induce initial tumor reduction, frequently followed by relapse. As demonstrated previously, BRAF(V600E)-inhibition induces apoptosis only in a fraction of treated cells, while the remaining arrest and survive providing a source or a niche for relapse. To identify factors contributing to the differential initial response towards BRAF/MEK inhibition, we established M14 melanoma cell line-derived single cell clones responding to treatment with BRAF inhibitor vemurafenib and MEK inhibitor trametinib predominantly with either cell cycle arrest (CCA-cells) or apoptosis (A-cells)...
July 15, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28711086/the-new-paradigm-of-systemic-therapies-for-metastatic-melanoma
#3
REVIEW
Virginia O Volpe, Daniel M Klufas, Upendra Hegde, Jane M Grant-Kels
New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.
August 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28709799/trough-dabrafenib-plasma-concentrations-can-predict-occurrence-of-adverse-events-requiring-dose-reduction-in-metastatic-melanoma
#4
Marine Rousset, Caroline Dutriaux, Pauline Bosco-Lévy, Sorilla Prey, Anne Pham-Ledard, Léa Dousset, Emilie Gérard, Stephane Bouchet, Mireille Canal-Raffin, Karine Titier, Mathieu Molimard
INTRODUCTION: Dabrafenib and trametinib bitherapy provides significant benefits in BRAFV600(mut) metastatic melanoma patients; however, adverse events (AE) occur, leading to dose reduction in 33% of patients. We aimed to investigate a relation between plasma dabrafenib and trametinib concentrations and occurrence of AE. METHODS: Plasma samples from metastatic BRAFV600(mut) melanoma patients treated with dabrafenib±trametinib were prospectively collected at trough concentration before any dose reduction...
July 12, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28707403/melanocytic-lesion-evolution-patterns-with-targeted-therapies-and-immunotherapies-for-advanced-metastatic-melanoma-an-observational-study
#5
Cathy Yunjia Zhao, Shelley Ji Eun Hwang, Deepal Wakade, Giuliana Carlos, Rachael Anforth, Pablo Fernández-Peñas
BACKGROUND/OBJECTIVES: Various cutaneous side-effects have been reported with anti-melanoma systemic therapies. This study investigated the changes in melanocytic lesion pigmentation in patients on four different therapies. METHODS: We analysed the serial dermatoscopic photographs of atypical melanocytic lesions taken from patients with advanced metastatic melanoma on four different systemic therapies (selective BRAF-inhibitor monotherapy, dabrafenib combined with trametinib [D&T], anti-programmed cell death protein 1 [anti-PD1] therapies, and anti-PD1 combined with ipilimumab) seen from February 2013 to May 2016...
July 14, 2017: Australasian Journal of Dermatology
https://www.readbyqxmd.com/read/28695986/acute-heart-failure-as-a-result-of-granulomatous-myocarditis-case-report-on-a-patient-with-metastatic-melanoma-treated-with-dabrafenib-and-trametinib
#6
J K Winkler, K Buder-Bakhaya, E Ellert, E Herpel, U M Martens, A Enk, J C Hassel
Treatment options for metastatic melanoma have changed substantially in recent years. Targeting immune checkpoints has improved prognosis of melanoma patients. For melanomas harboring BRAF mutations, inhibition of the mitogen-activated protein kinase pathway is a promising therapeutic option. Combined BRAF and MEK inhibition improves progression-free and overall survival. This article is protected by copyright. All rights reserved.
July 11, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28687621/cancer-associated-fibroblasts-share-characteristics-and-pro-tumorigenic-activity-with-mesenchymal-stromal-cells
#7
Lucia Borriello, Rie Nakata, Michael A Sheard, G Esteban Fernandez, Richard Sposto, Jemily Malvar, Laurence Blavier, Hiroyuki Shimada, Shahab Asgharzadeh, Robert C Seeger, Yves A DeClerck
Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship to MSC is not clear. Here we have isolated from primary human neuroblastoma (NB) tumors a population of αFAP- and FSP-1-expressing CAF that share phenotypic and functional characteristics with bone marrow-derived MSC (BM-MSC). Analysis of human NB tumors also confirmed the presence of αFAP- and FSP-1-positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages...
July 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/28666189/oral-metronomic-topotecan-sensitizes-crizotinib-antitumor-activity-in-alk-f1174l-drug-resistant-neuroblastoma-preclinical-models
#8
Libo Zhang, Bing Wu, Sylvain Baruchel
BACKGROUND: Anaplastic lymphoma kinase (ALK) inhibitor crizotinib has proven to be effective in the treatment of ALK-mutated neuroblastoma, but crizotinib resistance was commonly observed in patients. We aimed to overcome crizotinib resistance by combining with the MEK inhibitor trametinib or low-dose metronomic (LDM) topotecan in preclinical neuroblastoma models. METHODS: We selected a panel of neuroblastoma cell lines carrying various ALK genetic aberrations to assess the therapeutic efficacy on cell proliferation in vitro...
June 27, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28665153/risk-of-peripheral-edema-in-cancer-patients-treated-with-mek-inhibitors-a-systematic-review-and-meta-analysis-of-clinical-trials
#9
Yong Yang, Yi-Hua Liu, Xu Sun, Ming-Wei Yu, Lin Yang, Pei-Yu Cheng, Guo-Wang Yang, Xiao-Min Wang
BACKGROUND: MEK inhibitors are a group of drugs that have shown reliable effects in the treatment of metastatic melanoma and non-small-cell lung cancer. Peripheral edema is an adverse event associated with MEK inhibitors, however, there has been no systematic attempt to evaluate peripheral edema data observed with these agents. This meta-analysis aimed to determine the risk of peripheral edema in cancer patients treated with MEK inhibitors. MATERIAL AND METHODS: We searched PubMed, the Cochrane Library, EMBASE, and Clinical Trials...
June 30, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28652244/targeting-adenosine-in-braf-mutant-melanoma-reduces-tumor-growth-and-metastasis
#10
Arabella Young, Shin Foong Ngiow, Jason Madore, Julia Reinhardt, Jennifer Landsberg, Arash Chitsazan, Jai Rautela, Tobias Bald, Deborah Barkauskas, Elizabeth Ahern, Nicholas Huntington, Dirk Schadendorf, Georgina V Long, Glen M Boyle, Michael Hölzel, Richard A Scolyer, Mark J Smyth
Increasing evidence exists for the role of immunosuppressive adenosine in promoting tumor growth and spread in a number of cancer types, resulting in poor clinical outcomes. In this study, we assessed whether the CD73-adenosinergic pathway is active in melanoma patients and whether adenosine restricts the efficacy of clinically approved targeted therapies for commonly mutated BRAF(V600E) melanoma. In AJCC Stage III melanoma patients, CD73 expression (the enzyme that generates adenosine) correlated significantly with patients presenting nodal metastatic melanoma, suggesting that targeting this pathway may be effective in advanced stage disease...
June 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28648698/three-year-pooled-analysis-of-factors-associated-with-clinical-outcomes-across-dabrafenib-and-trametinib-combination-therapy-phase-3-randomised-trials
#11
Dirk Schadendorf, Georgina V Long, Daniil Stroiakovski, Boguslawa Karaszewska, Axel Hauschild, Evgeny Levchenko, Vanna Chiarion-Sileni, Jacob Schachter, Claus Garbe, Caroline Dutriaux, Helen Gogas, Mario Mandalà, John B A G Haanen, Céleste Lebbé, Andrzej Mackiewicz, Piotr Rutkowski, Jean-Jacques Grob, Paul Nathan, Antoni Ribas, Michael A Davies, Ying Zhang, Mathilde Kaper, Bijoyesh Mookerjee, Jeffrey J Legos, Keith T Flaherty, Caroline Robert
AIM: Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit...
June 21, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28628251/a-network-meta-analysis-of-short-and-long-term-efficacy-of-targeted-therapy-with-single-or-double-drug-regimens-in-the-treatment-of-stage-iii-iv-malignant-melanoma-based-on-16-randomized-controlled-trials
#12
Ting Xie, Chun-Yu Huang, Xu Kang, Jia-Sheng Luo, Xiao-Min Qin, Feng Han
For the treatment of stage III/IV malignant melanoma (MM), a network meta-analysis (NMA) was conducted to compare the short and long-term efficacy of targeted therapy with single or double-drug regimens. All conducted randomized controlled trials (RCTs) searched from PubMed and Cochrane Library were included in the study for direct and indirect comparison for MM. The odds ratio (OR) and surface under the cumulative ranking curves (SUCRA) value of the targeted therapy with single or double-drug regimens for treatment of stage III/IV MM were also analyzed...
June 19, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28626033/dabrafenib-plus-trametinib-achieves-overall-and-intracranial-responses
#13
(no author information available yet)
Dabrafenib plus trametinib achieves intracranial responses in BRAF-mutant melanoma brain metastases.
June 16, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28614138/acute-exudative-paraneoplastic-polymorphous-vitelliform-maculopathy-during-vemurafenib-and-pembrolizumab-treatment-for-metastatic-melanoma
#14
Harpal S Sandhu, Anton M Kolomeyer, Marisa K Lau, Carol L Shields, Lynn M Schuchter, Charles W Nichols, Tomas S Aleman
PURPOSE: To describe a patient with BRAF mutation-positive cutaneous melanoma who developed acute exudative polymorphous vitelliform maculopathy during vemurafenib and pembrolizumab treatment for metastatic melanoma. METHODS: Retrospective case report documented with wide-field fundus imaging, spectral domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: A 55-year-old woman with bilateral ductal breast carcinoma and BRAF mutation-positive metastatic cutaneous melanoma complained of bilateral blurred vision within 5 days of starting vemurafenib (BRAF inhibitor)...
June 13, 2017: Retinal Cases & Brief Reports
https://www.readbyqxmd.com/read/28611627/panniculitis-associated-with-mek-inhibitor-therapy-an-uncommon-adverse-effect
#15
Miruna Negulescu, Florian Deilhes, Vincent Sibaud, Emilie Tournier, Laurence Lamant, Serge Boulinguez, Nicolas Meyer
The combination of MEK inhibitor (cobimetinib, trametinib) and BRAF inhibitor (vemurafenib, dabrafenib) is now the first-line treatment in patients with BRAF V600-mutated metastatic melanoma. This association reduces cutaneous adverse events induced by BRAF inhibitors alone, including photosensitivity, hand-foot syndrome, hyperkeratosis, alopecia, skin papillomas, keratoacanthomas, and squamous-cell carcinomas. While panniculitis has exceptionally been reported with BRAF inhibitors, this rare side effect has never been described with the use of MEK inhibitors...
January 2017: Case Reports in Dermatology
https://www.readbyqxmd.com/read/28592387/dabrafenib-plus-trametinib-in-patients-with-braf-v600-mutant-melanoma-brain-metastases-combi-mb-a-multicentre-multicohort-open-label-phase-2-trial
#16
Michael A Davies, Philippe Saiag, Caroline Robert, Jean-Jacques Grob, Keith T Flaherty, Ana Arance, Vanna Chiarion-Sileni, Luc Thomas, Thierry Lesimple, Laurent Mortier, Stergios J Moschos, David Hogg, Iván Márquez-Rodas, Michele Del Vecchio, Céleste Lebbé, Nicolas Meyer, Ying Zhang, Yingjie Huang, Bijoyesh Mookerjee, Georgina V Long
BACKGROUND: Dabrafenib plus trametinib improves clinical outcomes in BRAF(V600)-mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases...
June 2, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28576487/mek-and-pi3k-catalytic-activity-as-predictor-of-the-response-to-molecularly-targeted-agents-in-triple-negative-breast-cancer
#17
Natsuki Sato, Masayuki Wakabayashi, Masatoshi Nakatsuji, Haruka Kashiwagura, Naohiro Shimoji, Shiho Sakamoto, Atsuko Ishida, Jangsoon Lee, Bora Lim, Naoto T Ueno, Hideki Ishihara, Takashi Inui
Hyper-activation of the MAPK and PI3K-AKT pathways is linked to tumour progression in triple-negative breast cancer (TNBC). However, clinically effective predictive markers for drugs targeted against protein kinases involved in these pathways have not been identified. We investigated the ability of MEK and PI3K catalytic activity to predict sensitivity to trametinib and wortmannin in TNBC. MEK and PI3K activities correlated strongly with each other only in cell lines showing wortmannin-specific sensitivity, as shown by a linear regression curve (R = 0...
May 30, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28553668/the-clinical-spectrum-of-erdheim-chester-disease-an-observational-cohort-study
#18
Juvianee I Estrada-Veras, Kevin J O'Brien, Louisa C Boyd, Rahul H Dave, Benjamin Durham, Liqiang Xi, Ashkan A Malayeri, Marcus Y Chen, Pamela J Gardner, Jhonell R Alvarado-Enriquez, Nikeith Shah, Omar Abdel-Wahab, Bernadette R Gochuico, Mark Raffeld, Elaine S Jaffe, William A Gahl
Erdheim-Chester Disease (ECD) is a rare, potentially fatal, multi-organ myeloid neoplasm occurring mainly in adults. The diagnosis is established by clinical, radiologic, and histologic findings; ECD tumors contain foamy macrophages that are CD68+, CD163+, CD1a-, and frequently S100-. The purpose of this report is to describe the clinical and molecular variability of ECD. Sixty consecutive ECD patients (45 males, 15 females) were prospectively evaluated at the NIH Clinical Center between 2011 and 2015. Comprehensive imaging and laboratory studies were performed, and tissues were examined for BRAF V600E and MAPK pathway mutations...
February 14, 2017: Blood Advances
https://www.readbyqxmd.com/read/28545687/synergistic-effect-of-mek-inhibitor-and-metformin-combination-in-low-grade-serous-ovarian-cancer
#19
Ismail Mert, Jasdeep Chhina, Ghassan Allo, Jing Dai, Shelly Seward, Mark S Carey, Marta Llaurado, Shailendra Giri, Ramandeep Rattan, Adnan R Munkarah
OBJECTIVE: Low-grade serous ovarian cancer (LGSOC) constitutes 5-8% of epithelial ovarian cancers and is refractory to chemotherapy. We and others have shown metformin to cause significant growth inhibition in high-grade ovarian cancer both in vitro and in vivo. Here, we aimed to analyze if metformin was effective in inhibiting proliferation of LGSOC alone and in combination with MEK inhibitor. METHODS: Three LGSOC lines (VOA1056, VOA1312 and VOA5646) were treated with metformin, trametinib or 2-deoxyglucose (2DG) alone or in combination with metformin...
August 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28538872/melanoma-tumor-microenvironment-and-new-treatments
#20
Mara Huffenbaecher Giavina-Bianchi, Pedro Francisco Giavina-Bianchi, Cyro Festa
In the recent past years, many discoveries in the tumor microenvironment have led to changes in the management of melanoma and it is rising up hopes, specially, to those in advanced stages. FDA approved seven new drugs from 2011 to 2014. They are: Vemurafenib, Dabrafenib and Trametinib, kinases inhibitors used for patients that have BRAFV600E mutation; Ipilimumab (anti-CTLA4), Pembrolizumab (anti-PD-1) and Nivolumab (anti-PD-1), monoclonal antibodies that stimulate the immune system; and Peginterferon alfa-2b, an anti-proliferative cytokine used as adjuvant therapy...
March 2017: Anais Brasileiros de Dermatologia
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