BackgroundSeveral recent randomized clinical trials have preliminarily demonstrated that initial targeted therapy with combined BRAF and MEK inhibition is more effective in metastatic melanoma (MM) than single agent. To guide therapeutic decisions, we did a comprehensive network meta-analysis to identify evidence to robustly support whether combined BRAF and MEK inhibition is the best initial targeted therapeutic strategy for patients with MM.MethodsThe databases of PubMed and trial registries were researched for randomized clinical trials of targeted therapy. Data of outcome were extracted on progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Network meta-analysis using a Bayesian statistical model was performed to evaluate relative hazard ratio (HR) for PFS and OS, odds ratio (OR) for ORR.ResultsFinally, 16 eligible trials comprising 5976 participants were included in this meta-analysis. PFS were significantly prolonged in patients who received combined BRAF-MEK inhibition compared with those who received BRAF inhibition (HR: 0.58, 95%CI: 0.51-0.67, P < 0.0001) or MEK inhibition alone (HR: 0.29, 95%CI: 0.22-0.37, P < 0.0001). Combined BRAF-MEK inhibition also improved the OS over BRAF inhibition (HR: 0.67, 95%CI: 0.56-0.81, P < 0.0001) or MEK inhibition alone (HR: 0.48, 95%CI: 0.36-0.65, P < 0.0001). The ORR was superior in combined BRAF and MEK inhibition comparing with BRAF inhibition (OR: 2.00, 95%CI: 1.66-2.44, P < 0.0001) or MEK inhibition alone (OR: 20.66, 95%CI: 12.22-35.47, P < 0.0001).ConclusionsThis study indicates that concurrent inhibition of BRAF and MEK improved the most effective therapeutic modality as compared as single BRAF or MEK inhibition for patients with MM.
The East Kunlun Orogenic Belt is located in the western part of the Central Orogenic Belt of China, with a large number of Triassic igneous rocks parallel to the Paleo-Tethys ophiolite belt, which provides a large amount of geological information for the tectonic evolution of the Paleo-Tethys Ocean. The granitoids studied in this paper are located in the Ela Mountain area in the eastern part of the East Kunlun Orogenic Belt. Zircon U-Pb dating results show that these different types of granitoids were crystallized in the Triassic. The 247.5 Ma porphyritic granites from Zairiri (ZRR) displayed calc-alkaline I-type granite affinities, with the zircon εHf(t) values being mainly positive (−0.5 to + 3.8, TDM2 of 1309–1031 Ma), indicating that they are derived from the partial melting of the juvenile crust and mixed with ancient crustal components. The 236.8 Ma Henqionggou (HQG) granodiorites and 237.5 Ma Daheba (DHB) granodiorites are high-K calc-alkaline I-type granite, and both have mafic microgranular enclaves (MMEs), showing higher and more varied Mg# (39.73–62.73), combined with their negative Hf isotopes (εHf(t) = −2.6 to −1.6, TDM2 = 1430–1369 Ma), suggesting that their primary magmas were the products of partial melting of the Mesoproterozoic lower crust that mixed with mantle-derived rocks. The 236.4 Ma DHB porphyritic diorites showed characteristics of high-K calc-alkaline I-type granitoids, with moderate SiO2 contents, medium Mg# values (40.41–40.65), with the Hf isotopes (εHf(t) = −2.9 to −0.5; TDM2 = 1451–1298 Ma) indistinguishably relative to contemporaneous host granodiorites and MMEs. The petrographic and geochemical characteristics indicate that the porphyritic diorites are the product of well-mixed magma derived from the Mesoproterozoic lower crust and lithospheric mantle. Based on the results of this paper and previous data, the chronology framework of Late Permian–Triassic magmatic rocks in the eastern part of the East Kunlun Orogenic Belt was constructed, and the magmatic activities in this area were divided into three peak periods, with each peak representing an extensional event in a particular tectonic setting, for example, P1 (slab roll-back in subduction period; 254–246 Ma), P2 (slab break-off in transition period of subduction and collision; 244–232 Ma), P3 (delamination after collision; 230–218 Ma).
The Ela Mountain area is located at the easternmost point of the East Kunlun Orogen, in which voluminous igneous rocks developed in the Triassic period, and it is a good place to investigate the tectonic evolution of the Paleo-Tethys Ocean. In this study, petrological, geochemical, zircon U-Pb geochronology and zircon Hf isotope studies were carried out on the volcanic rocks in the Ela Mountain area. Dacite (239.3 ± 1.4 Ma) exhibits calc-alkaline I-type characteristics, and rhyolite (237.8 ± 2.1 Ma) is similar to high-K calc-alkaline highly fractionated I-type volcanic rock. The petrogenesis shows that both rhyolite and dacite originated from the partial melting of the mafic lower crust of the Mesoproterozoic under relatively high temperature and low pressure. Dacite and rhyolite were derived from the same or similar parent magma, and they are volcanic rocks with different differentiation degrees formed in the same magmatic pulse activity. Differing from rhyolite and dacite, basaltic andesite shows a relatively young age (234 ± 1.2 Ma), mainly originating from the partial melting of the lithospheric mantle modified by subducted slab-derived fluids; the magma was contaminated with a small amount of crustal source components and experienced the fractional crystallization of mafic minerals before the eruption to the surface. This study on the tectonic environment of these volcanic rocks shows that they were formed in the environment of slab failure in the late stage of syn-collision, and that they are different types of volcanic rocks from different sources under similar tectonic environments. The volcanic rocks of the Ela Mountain area in this contribution provide important evidence for Middle Triassic to Late Triassic syn-collisional magmatism in the slab failure stages. The results of this study constrain the lower age limit of the closure of the Paleo-Tethys Ocean and the initial time of extension of the late stage of syn-collision, providing important information regarding regional tectonic evolution processes and volcanic activity history. They can be applied to regional tectonic evolution, petrology, volcanic stratigraphy and mineral deposits related to volcanic rocks.
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