The treatment of metastatic non-small cell lung cancer (NSCLC) has undergone a paradigm shift over the last decade. Better molecular characterization of the disease has led to the rapid improvement of personalized medicine and the prompt delivery of targeted therapies to patients with NSCLC. The discovery of the EML4-ALK fusion gene in a limited subset of patients affected by NSCLC and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistances regularly develop, hence disease progression occurs. Afterward, modern tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, and lorlatinib, have been approved by the Food and Drug Administration (FDA) for the management of anaplastic lymphoma kinase (ALK)-positive NSCLCs. Several compounds are currently under investigation to achieve the optimal strategy of therapy. Additionally, the results of ongoing clinical trials with novel-generation TKI will provide more evidence on the best sequence in the treatment of ALK-positive NSCLC patients. In this review, we provide a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized.
The effects of canopy manipulation and shading on crop quantity and quality as well as plant physiology in Vitis vinifera have already been studied by many authors while the plant nutritional status changes induced by such treatments present many unexplained aspects. Partial cluster and leaf removals were performed on Vitis vinifera L. cv. Cabernet Sauvignon at veraison (40% berries coloured) for two years to give four treatments: Control (C), Cluster Thinning (CT), Leaf Removal (LR), and Cluster Thinned + Leaf Removal (CT+LR) plots. At veraison, one half of these plots were shaded using a 50% shading net. The correlations between elemental contents of different organs showed that only potassium (K) in the leaves and stems were positively related, while for the other macro-and micro-elements, no relationship or negative links were obtained. Shading needs only 14 days to modify the nitrogen (N) and phosphorus (P) in leaves. At harvest, N was depressed in leaves of cluster-thinned vines and enhanced in leaf-removed ones. Such changes are discussed on the basis of photosynthetic data which support the hypothesis that canopy manipulation involves modifications in both leaf biochemical and photochemical activities.
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