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Evelina Cardoso, Thomas Mercier, Anna Dorothea Wagner, Krisztian Homicsko, Olivier Michielin, Kim Ellefsen-Lavoie, Laurène Cagnon, Manuel Diezi, Thierry Buclin, Nicolas Widmer, Chantal Csajka, Laurent Decosterd
A sensitive and selective method of high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS) has been developed for the simultaneous quantification of six anticancer protein kinase inhibitors (PKIs), dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib, and two active metabolites (regorafenib-M2 and regorafenib-M5) in human plasma. Plasma protein precipitation with methanol enables the sample extraction of 100 μL aliquot of plasma. Analytes are detected by electrospray triple-stage quadrupole mass spectrometry and quantified using the calibration curves with stable isotope-labeled internal standards...
February 8, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Zhenhua Wu, Mingzhu Huang, Yiwei Gong, Chen Lin, Weijian Guo
Mutations in the oncogene BRAF(V600E) are found in ~10% of colorectal cancers (CRCs) and are associated with poor prognosis. However, BRAF(V600E) has a limited response to the small-molecule drug, vemurafenib, a BRAF inhibitor, and BRAF inhibition is thought to cause a feedback activation of EGFR signaling that supports continued proliferation. In this study, we explored the effect of combined use of dabrafenib, a BRAF inhibitor, and cetuximab, an EGFR inhibitor, on BRAF(V600E)-mutant CRC stem cells and its possible mechanisms...
March 9, 2018: Acta Biochimica et Biophysica Sinica
Emilia Cocorocchio, Laura Pala, Angelo Battaglia, Sara Gandini, Fedro Alessandro Peccatori, Pier Francesco Ferrucci
No abstract text is available yet for this article.
March 11, 2018: Acta Oncologica
Yang Meng, Nadine Hertel, John Ellis, Edith Morais, Helen Johnson, Zoe Philips, Neil Roskell, Andrew Walker, Dawn Lee
BACKGROUND: Nivolumab was the first programmed death receptor 1 (PD-1) immune checkpoint inhibitor to demonstrate long-term survival benefit in a clinical trial setting for advanced melanoma patients. OBJECTIVE: To evaluate the cost effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. METHODS: A Markov state-transition model was developed to estimate the lifetime costs and benefits of nivolumab versus ipilimumab and dacarbazine for BRAF mutation-negative patients and versus ipilimumab, dabrafenib, and vemurafenib for BRAF mutation-positive patients...
March 9, 2018: European Journal of Health Economics: HEPAC: Health Economics in Prevention and Care
Nghi C Nguyen, Melissa K Yee, Abuzar M Tuchayi, John M Kirkwood, Hussein Tawbi, James M Mountz
Introduction: This pilot study aimed at exploring the utility of the proliferation tracer F-18 fluorothymidine (FLT) and positron-emission tomography (PET)/magnetic resonance imaging (MRI) (FLT-PET/MRI) for early treatment monitoring in patients with melanoma brain metastasis (MBM) who undergo targeted therapy or immunotherapy. Material and Methods: Patients with newly diagnosed MBM underwent baseline and follow-up FLT-PET/MRI scans at 3-4 weeks of targeted therapy or immunotherapy...
2018: Frontiers in Oncology
Lisa Walter, Lucie Heinzerling
BACKGROUND/AIM: Recent evidence suggests that melanoma patients treated with BRAF inhibitors experience radiosensitization with an increased frequency of side-effects. This could also imply increased effectiveness when treating melanoma. MATERIALS AND METHODS: To test whether the BRAF inhibitors dabrafenib and vemurafenib together with ionizing radiation more effectively inhibit melanoma cells, primary human melanoma tumor cell lines expressing wild-type (WT) or mutant V600E BRAF were analyzed by cell survival, cell death, and cell-cycle testing...
March 2018: Anticancer Research
Taku Fujimura, Yumi Kambayashi, Kayo Tanita, Yota Sato, Takanori Hidaka, Astushi Otsuka, Hidenori Tanaka, Sadanori Furudate, Akira Hashimoto, Setsuya Aiba
Although uveitis is reported as a rare adverse event (AE) associated with dabrafenib/trametinib therapy or nivolumab, the occurrence of severe uveitis is extremely rare. We describe two cases of Vogt-Koyanagi-Harada (VKH)-like uveitis developing after the sequential administration of nivolumab and dabrafenib/trametinib therapy. Interestingly, both cases had HLA-DRB1*04:05, which is strongly associated with VKH disease, and achieved biologically complete remission after the treatment for uveitis. Our cases suggest a possible correlation between VKH-like uveitis as an AE and the clinical outcomes of sequential administration of nivolumab and dabrafenib/trametinib therapy for the treatment of advanced melanoma...
February 27, 2018: Journal of Dermatology
Liborija Lugović-Mihić, Tomislav Duvančić, Iva Ferček, Petra Vuković, Iva Japundžić, Diana Ćesić
When taking different drugs, their possible side effects on the skin should be considered, including skin reactions connected to photosensitivity. This photosensitivity caused by drugs can appear as phototoxic reactions (which occur more often) or photoallergic reactions (which occur less often and include allergic mechanisms). The following drugs stand out as medications with a high photosensitivity potential: nonsteroidal anti-inflammatory drugs (NSAIDs), cardiovascular drugs (such as amiodarone), phenothiazines (especially chlorpromazine), retinoids, antibiotics (sulfonamides, tetracyclines, especially demeclocycline and quinolones), etc...
June 2017: Acta Clinica Croatica
Sonia Brugnara, Mariacristina Sicher, Elena Maria Bonandini, Davide Donner, Franca Chierichetti, Mattia Barbareschi, Carlo Renè Girardelli, Orazio Caffo
Here, we report the case of a patient, diagnosed with BRAF V600E -mutated metastatic malignant melanoma M1a, who achieved a complete metabolic response after 7 months of treatment with the combination of dabrafenib and trametinib. After 31 months, the treatment was interrupted for patient's decision. To date October 2017, 18 months after the interruption of the treatment with the combination of dabrafenib and trametinib, follow-up Positron Emission Tomography (PET) scans are still documenting complete metabolic response...
2018: Drugs in Context
Ankush Bhatia, Gary Ulaner, Raajit Rampal, David M Hyman, Omar Abdel-Wahab, Benjamin H Durham, Ahmet Dogan, Neval Ozkaya, Mario E Lacouture, Julio Hajdenberg, Chezi Ganzel, Eli L Diamond
No abstract text is available yet for this article.
February 22, 2018: Haematologica
Hisashi Uhara
New therapeutic strategies including immunotherapy and selective molecular target inhibitors have brought about a new era in the treatment of patients with advanced melanoma. In Japan, the immune checkpoint inhibitors ipilimumab, nivolumab and pembrolizumab, the BRAF inhibitor (BRAFi) vemurafenib, dabrafenib and MEK inhibitor (MEKi) trametinib have been available for the treatment of unresectable and metastatic melanoma. The BRAFi + MEKi combination shows high response rates (60-70%) and rapid response induction associated with symptom control, with a progression-free survival of 12 months...
February 22, 2018: International Journal of Clinical Oncology
Yang Yang, Yi Meng, Hang Zhang, Xiaoyan Shen, Rutian Li, Lixia Yu, Baorui Liu, Lifeng Wang
Epithelial growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) expressing sensitive EGFR-mutants. Other drugs target different driver mutants, including the serine/threonine-protein kinase B-raf (BRAF) inhibitor dabrafenib, which has exhibited promising efficacy for treating patients with metastatic BRAF-mutated NSCLC. Therefore, identifying patients carrying mutations that may be treated using targeted therapies is important...
March 2018: Oncology Letters
Simone Fulda
Necroptosis represents a form of programmed cell death that can be engaged by various upstream signals, for example by ligation of death receptors, by viral sensors or by pattern recognition receptors. It depends on several key signaling proteins, including the kinases Receptor-Interacting Protein (RIP)1 and RIP3 and the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Necroptosis has been implicated in a number of physiological and pathophysiological conditions and is disturbed in many human diseases...
February 21, 2018: Cell Cycle
Jennifer L McQuade, Carrie R Daniel, Kenneth R Hess, Carmen Mak, Daniel Y Wang, Rajat R Rai, John J Park, Lauren E Haydu, Christine Spencer, Matthew Wongchenko, Stephen Lane, Dung-Yang Lee, Mathilde Kaper, Meredith McKean, Kathryn E Beckermann, Samuel M Rubinstein, Isabelle Rooney, Luna Musib, Nageshwar Budha, Jessie Hsu, Theodore S Nowicki, Alexandre Avila, Tomas Haas, Maneka Puligandla, Sandra Lee, Shenying Fang, Jennifer A Wargo, Jeffrey E Gershenwald, Jeffrey E Lee, Patrick Hwu, Paul B Chapman, Jeffrey A Sosman, Dirk Schadendorf, Jean-Jacques Grob, Keith T Flaherty, Dana Walker, Yibing Yan, Edward McKenna, Jeffrey J Legos, Matteo S Carlino, Antoni Ribas, John M Kirkwood, Georgina V Long, Douglas B Johnson, Alexander M Menzies, Michael A Davies
BACKGROUND: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. METHODS: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy...
February 12, 2018: Lancet Oncology
Markus Hecht, Friedegund Meier, Lisa Zimmer, Bülent Polat, Carmen Loquai, Carsten Weishaupt, Andrea Forschner, Ralf Gutzmer, Jochen S Utikal, Simone M Goldinger, Michael Geier, Jessica C Hassel, Panagiotis Balermpas, Felix Kiecker, Ricarda Rauschenberg, Ursula Dietrich, Patrick Clemens, Carola Berking, Gerhard Grabenbauer, Dirk Schadendorf, Stephan Grabbe, Gerold Schuler, Rainer Fietkau, Luitpold V Distel, Lucie Heinzerling
BACKGROUND: Concomitant radiation with BRAF inhibitor (BRAFi) therapy may increase radiation-induced side effects but also potentially improve tumour control in melanoma patients. METHODS: A total of 155 patients with BRAF-mutated melanoma from 17 European skin cancer centres were retrospectively analysed. Out of these, 87 patients received concomitant radiotherapy and BRAFi (59 vemurafenib, 28 dabrafenib), while in 68 patients BRAFi therapy was interrupted during radiation (51 vemurafenib, 17 dabrafenib)...
February 13, 2018: British Journal of Cancer
Ryan B Corcoran, Thierry Andre, Chloe E Atreya, Jan H M Schellens, Takayuki Yoshino, Johanna C Bendell, Antoine Hollebecque, Autumn J McRee, Salvatore Siena, Gary Middleton, Kei Muro, Michael S Gordon, Josep Tabernero, Rona Yaeger, Peter J O'Dwyer, Yves Humblet, Filip De Vos, A Scott Jung, Jan C Brase, Savina Jaeger, Severine Bettinger, Bijoyesh Mookerjee, Fatima Rangwala, Eric Van Cutsem
Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only ~5% with BRAFV600E colorectal cancer (CRC) respond. Preclinical studies suggest that lack of efficacy in BRAFV600E CRC is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E CRC...
February 5, 2018: Cancer Discovery
Naoya Yamazaki, Arata Tsutsumida, Akira Takahashi, Kenjiro Namikawa, Shusuke Yoshikawa, Yutaka Fujiwara, Shunsuke Kondo, Akihira Mukaiyama, Fanghong Zhang, Yoshio Kiyohara
The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end-point in phase 2 was to assess confirmed overall response rate (ORR)...
February 5, 2018: Journal of Dermatology
Salvador Martín Algarra, Virtudes Soriano, Luis Fernández-Morales, Miguel-Ángel Berciano-Guerrero, Karmele Mujika, José Luis Manzano, Teresa Puértolas Hernández, Ainara Soria, Delvys Rodríguez-Abreu, Enrique Espinosa Arranz, Javier Medina Martínez, Ivan Márquez-Rodas, Jordi Rubió-Casadevall, María Eugenia Ortega, José Miguel Jurado García, María José Lecumberri Biurrun, Isabel Palacio, María Rodríguez de la Borbolla Artacho, Javier Pérez Altozano, Victoria Eugenia Castellón Rubio, Almudena García, Pablo Luna, Anabel Ballesteros, Ovidio Fernández, Jose Antonio López Martín, Alfonso Berrocal, Ana Arance
The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively...
December 2017: Medicine (Baltimore)
Asher M Marks, Ranjit S Bindra, Michael L DiLuna, Anita Huttner, Vikram Jairam, Kristopher T Kahle, Mark W Kieran
Efficacy of BRAF V600E targeted therapies in brain tumors harboring the mutation has been shown in several case reports and is currently being studied in larger clinical trials. Monotherapy with vemurafenib has been associated with significant side effects, including rashes, papillomas, and squamous cell carcinomas. Here we describe an adolescent female with anaplastic ganglioglioma and significant skin reaction to vemurafenib with subsequent tumor response and tolerance to the BRAF/MEK inhibitor combination of dabrafenib and trametinib without recurrence of previous reaction...
January 30, 2018: Pediatric Blood & Cancer
Jacob R Stewart, Era C Murzaku, Titilola T Sode, Katherine A Gordon
No abstract text is available yet for this article.
January 2018: JAAD Case Reports
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