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Craniopharyngioma
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Hermann L. Müller, Claire Alapetite, Jeffrey Wisoff
Using a transcriptomic approach, Apps et al.50 provided a molecular rationale explaining the histological similarities between adamantinomatous craniopharyngiomas and the normally developing tooth. Additionally, this research has revealed that inhibition of the MAPK/ERK pathway using trametinib results in decreased proliferation and increased apoptosis in explant cultures of human adamantinomatous craniopharyngiomas.50 As trametinib is a relatively safe drug in children, these in vitro findings merit further studies. Recent work of the authors shows that there is activation of inflammatory mediators in the cyst fluid and solid parts of adamantinomatous craniopharyngioma51 and that immune checkpoint inhibitors PD-L1 are expressed at high levels in papillary craniopharyngiomas and in the epithelial lining of the cysts of adamantinomatous craniopharyngiomas.52
Melanoma-associated emergencies
Published in Biju Vasudevan, Rajesh Verma, Dermatological Emergencies, 2019
Vidya Kharkar, M. R. L. Sujata
Trametinib was approved by the FDA in May 2013 for BRAFV600E or BRAFV600 K positive unresectable or metastatic melanomas. Its mechanism of action is different from that of vemurafenib or dabrafenib. Trametinib inhibits MEK, i.e., the extracellular signal-regulated kinase that is downstream of BRAF. Its dose is 2 mg orally once daily. The contraindications include melanoma harboring wild-type BRAF and patients previously treated with BRAF inhibitors. In January 2014, the FDA granted approval to a combination of dabrafenib and trametinib for unresectable or metastatic melanoma with BRAFV600 mutations. Dabrafenib and trametinib in combination improve survival significantly compared to vemurafenib alone in BRAFV600 mutant metastatic melanomas [61]. A combination of BRAF and MEK inhibitors appears to be superior to monotherapy.
D
Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
There is a case report of a haemodialysis patient being treated with dabrafenib 75 mg twice daily and trametinib 1 mg once daily. The patient developed diarrhoea so treatment was stopped. Once resolved the dabrafenib was restarted at 50 mg once daily. After 2 months there was some tumour response. The patient developed skin toxicities so trametinib was restarted at a dose of 0.5 mg once daily with anti-diarrhoeal treatment to control the side effects.1
Choriocapillaris Assessment In Patients Under Mek-Inhibitor Therapy For Cutaneous Melanoma: An Optical Coherence Tomography Angiography Study
Published in Seminars in Ophthalmology, 2021
Giuseppe Fasolino, Gil Awada, Jorgos Socrates Koulalis, Bart Neyns, Peter Van Elderen, Robert W Kuijpers, Pieter Nelis, Marcel Ten Tusscher
Our study includes 34 eyes of 17 patients with advanced BRAFV600 wild-type cutaneous melanoma. All patients had developed progressive disease after treatment with immune checkpoint inhibitors (nivolumab, pembrolizumab and/or ipilimumab) and were subsequently treated with the MEK-inhibitor trametinib 2 mg once daily in a single center phase 2 clinical trial (NCT04059224). Per protocol, in case of dose-limiting skin toxicity the BRAF-inhibitor, dabrafenib 50 mg twice daily, was added to trametinib. The patients were evaluated in the department of ophthalmology of the University Hospital of Brussels. Four patients (24%) started treatment with Trametinib between January and February 2019. The remaining thirteen patients (76%) were started treatment between the months of May and December 2019. The aim of the study was to achieve a mean follow-up period of 4 months, with an ophthalmologic check-up every 6 weeks.
The MAP kinase signal transduction pathway: promising therapeutic targets used in the treatment of melanoma
Published in Expert Review of Anticancer Therapy, 2020
Erin McClure, Michael J Carr, Jonathan S Zager
In the phase I trial dose reductions were necessitated in 22% of patients, with the most common reported AE being rash or dermatitis acneiform, found in 82%. Eighteen percent of patients experienced grade 3 treatment related AEs, and 2% had grade 4 AEs. [66] The phase II trial had 15% of patients undergo dose reductions due to AEs, with the most common reason being skin-related toxicity. There were no treatment-related deaths and only a single grade 4 AE, which was a pulmonary embolism. The most common grade 3 AEs were skin-related, diarrhea, peripheral edema, and reversible left ventricular ejection fraction reduction. There were no reports of cutaneous SCC, consistent with phase I results. [67] In the phase III trial, 35% of patients required dose interruptions and 27% of patients had dose reductions in the trametinib group. Ninety-six percent of patients had at least one AE of any severity. The most common AEs in the trametinib group were rash, diarrhea, peripheral edema, fatigue, and dermatitis acneiform. [68]
Update on BRAF and MEK inhibition for treatment of melanoma in metastatic, unresectable, and adjuvant settings
Published in Expert Opinion on Drug Safety, 2019
Kristy Kummerow Broman, Lesly A Dossett, James Sun, Zeynep Eroglu, Jonathan S Zager
In an open-label phase III trial (METRIC), 322 patients with BRAFV600E/K-mutant metastatic melanoma were randomized to receive either trametinib (n = 214) or chemotherapy (dacarbazine or paclitaxel) (n = 108) [51]. Sixty-five patients (60%) in the chemotherapy group crossed over to trametinib with disease progression. Median PFS was 4.8 months in the trametinib group versus 1.4 months in the chemotherapy group (HR = 0.45, 95% CI 0.33–0.63, p < 0.001) and 6-month OS was 81% in the trametinib group and 67% in the chemotherapy group (HR = 0.54, 95% CI 0.32–0.92, p = 0.01), despite significant crossover (Table 1). Based on these results, trametinib was approved by the FDA in 2013 for patients with unresectable stage IIIC or metastatic melanoma with BRAFV600E/K mutations.