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Discrepancy in Length of the Femur
Published in Benjamin Joseph, Selvadurai Nayagam, Randall T Loder, Anjali Benjamin Daniel, Essential Paediatric Orthopaedic Decision Making, 2022
Christopher Prior, Nicholas Peterson, Selvadurai Nayagam
Bone age assessments suggested she had a skeletal immaturity of about two years behind her chronological age. When leg length equality was established, the femoral 8-plates were removed to avoid over-shortening. At the same time, a varus deformity at the knee, which had recently developed arising from the proximal tibia, was treated using guided growth (Figure 36.9). This surgery coincided with the patient starting a trial of MEK inhibitor therapy.4
Monographs of Topical Drugs that Have Caused Contact Allergy/Allergic Contact Dermatitis
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
General aspects of corticosteroids used on the skin and mucous membranes are discussed in Chapter 2.4. A practical guideline for diagnosing allergic reactions to corticosteroids is presented in ref. 28. Hydrocortisone butyrate 1% pet. is included in the American core allergen series (www.smartpracticecanada.com) as screening agent for corticosteroid hypersensitivity (37). A considerable number of positive patch test reactions to hydrocortisone butyrate may be missed when readings are not performed at day 7 (22,23). MEK (methyl ethyl ketone) may be a suitable vehicle for patch testing hydrocortisone butyrate (32) and alcohol is superior over petrolatum (37,38,53). Intradermal testing with hydrocortisone butyrate may reveal additional cases of sensitization not picked up by patch testing (50,51). Hydrocortisone butyrate was suggested as a useful screening agent for corticosteroid allergy in 1986 (53), but was later replaced with tixocortol pivalate and budesonide.
Biomarkers for the Management of Malignancies with BRAF Mutation
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
MEK inhibitors have also been extensively investigated in BRAF-mutant-driven tumors [21]. In melanoma, phase 1 and 2 trials of the MEK inhibitor trametinib reported improvement in both PFS and OS [23, 24]. MEK inhibitors did not show the paradoxical MAPK pathway activation response observed with single agent vemurafenib or dabrafenib. However, the efficacy of MEK inhibitors as single agents is relatively modest compared to the combination of BRAF and MEK inhibitors in BRAF-mutant cancers [23–25, 26]. Therefore, BRAF and MEK inhibitor combinatorial treatments, in the form of trametinib/dabrafenib, cobimetinib/vemurafenib, and encorafenib/binimetinib were approved by the US Food and Drug Administration (FDA) for patients with advanced BRAF V600E/K melanoma [23, 26, 27]. In addition, dabrafenib and trametinib in combination are approved for adjuvant treatment of melanoma with BRAF V600E or V600K mutations, and involvement of lymph node(s) following complete resection [28].
Dysregulated MAPK signaling pathway in acute myeloid leukemia with RUNX1 mutations
Published in Expert Review of Hematology, 2022
Mingmin He, Yongqin Jia, Yan Wang, Xiongwei Cai
MAPKs are highly conserved protein kinases, including 19 species of MAPKKK (also named MAP3K or MEKK), 7 kinds of MAPKK (MAP2K), and 14 kinds of MAPK. They transmit extracellular signals to intracellular molecules to regulate cell growth. There are four distinct MAPK signaling cascades, including extracellular signal-related kinases (ERK1/2), Jun amino-terminal kinases (JNK1/2/3), p38 kinase, and ERK5 [32]. Accumulated evidences showed that MAPK signaling pathway determined the chemo-response [33]. Dual inhibition of the MAPK pathways enhanced chemotherapy response in preclinical models of pancreatic cancer [34]. ERK inhibition has attracted attentions as new treatment strategies for colorectal cancer [35,36]. MEK inhibitor (PD0325901) was tested in a phase II clinical trial for advanced non-small cell line lung cancer (NSCLC) [37]. Inhibitor for p38 MAPK improved behavior and synaptic function of mouse with Alzheimer’s disease. Inhibition of JNK pathway provided a potent regulator for brain inflammation in neurological disorders [38,39].
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
BRAF- and MEK-inhibitors have a distinct toxicity profile. While BRAF-inhibitors commonly cause fever, photosensitivity or arthralgia, MEK-inhibitors may give rise to cutaneous toxicity (acneiform dermatitis, hand-foot-syndrome), cardiovascular toxicity (arterial hypertension, heart failure, QTc-prolongation), digestive toxicity (diarrhea, liver toxicity), muscle toxicity (muscle cramps, creatin kinase increase, rhabdomyolysis), amongst others. MEK-inhibitors are particularly toxic for the eye, with an incidence of up to 90%.5 Most of these adverse events are a- or paucisymptomatic, self-limited or reversible with temporary drug withdrawal or decrease in dosage. Some, however, such as the retinal pigment epithelium detachment (RPED) and retinal vein occlusion (RVO) could lead to permanent vision loss. The term MEKAR (MEK-inhibitor Associated Retinopathy) describes the class effect dose/time-dependent retinal adverse events observed with the use of MEK inhibitors. The clinical features of MEKAR include blurred vision, transient visual disturbances, flashes, and subretinal fluid, mimicking central serous chorioretinopathy (CSC). However, in contrast to central serous chorioretinopathy, signs are usually found bilateral and multifocal. In optical coherence tomography the fluid is typically localized between the retinal pigment epithelium (RPE) and the interdigitation zone without gravitational dependency.6 Moreover, MEK-inhibitor induced serous detachment may not be associated with a pachychoroid phenotype and the pathophysiology does not show alterations in choroidal thickness.
Advancements of compounds targeting Wnt and Notch signalling pathways in the treatment of inflammatory bowel disease and colon cancer
Published in Journal of Drug Targeting, 2021
Zhuonan Pu, Fang Yang, Liang Wang, Yunpeng Diao, Dapeng Chen
Studies on mitogen activated protein kinase kinase (MEK) inhibitors have shown that their activation of the Wnt signalling pathway can prevent the development of hepatocellular carcinoma [55,56]. In the intestine, the MEK inhibitors trametinib, AZD6244, GSK112012, AS703026 and BAY 86-9766 have been found to be effective in the treatment of colon cancer in mice and suppress proliferation of different human colon cancer cell lines, including HCT116, HT29, SW480, RKO, DLD1, HEK293T, and PIK3CA [55,57]. These inhibitors interfere with the production of axin and reduce dissociation of GSK3β from axin by specifically inhibiting MEK, thereby activating the Wnt pathway which leads to the restoration of ISCs plasticity [58]. In recent years, some MEK inhibitors have entered clinical studies. For instance, PD0325901 has been evaluated in phase II trials for colon cancer [59]; CI1040 was well tolerated in patients with colon cancer in a multicentre phase II study [60]; selumetinib was well tolerated in KRAS mutant colon cancer in a phase I study [61].