RESUMO
OBJECTIVE: To date, no direct comparisons have compared the effectiveness of all ALK inhibitors (ALKis) against ALK-positive non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the efficacy and safety of ALKis in ALK-positive NSCLC. METHODS: The effectiveness of ALKis was evaluated by assessing progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and PFS with baseline brain metastasis (BM). The serious adverse events (SAEs: Grade ≥ 3) and adverse events (AEs) leading to discontinuation were pooled to evaluate safety. We conducted an indirect treatment comparison between all ALKis by using a Bayesian model. RESULTS: Twelve eligible trials including seven treatments were identified. All of the ALKis improved PFS and ORR relative to chemotherapy. Consistent with alectinib, brigatinib, lorlatinib, and ensartinib showed significant differences versus crizotinib and ceritinib. Lorlatinib seemed to prolong PFS compared with alectinib (0.64, 0.37 to 1.07), brigatinib (0.56, 0.3 to 1.05), and ensartinib (0.53, 0.28 to 1.02). No significant difference was found among them in OS except for alectinib versus crizotinib. Moreover, alectinib was significantly more effective than crizotinib (1.54, 1.02 to 2.5) in achieving the best ORR. Subgroup analyses based on BM indicated that PFS was dramatically lengthened by lorlatinib. Compared with other ALKis, alectinib notably reduced the rate of SAEs. There was no striking difference between discontinuation for AEs, except for ceritinib versus crizotinib. The ranking of validity showed that lorlatinib had the longest PFS (98.32%) and PFS with BM (85.84%) and the highest ORR (77.01%). The rank of probabilities showed that alectinib had the potentially best safety in terms of SAEs (97.85%), and ceritinib had less discontinuation (95.45%). CONCLUSION: Alectinib was the first choice for patients with ALK-positive NSCLC and even for those with BM, whereas lorlatinib was the second choice. Long-term follow-up and prospective studies are warranted to compare ALKis and to verify our conclusions directly.
Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Metanálise em Rede , Teorema de Bayes , Quinase do Linfoma Anaplásico/genética , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Encefálicas/secundário , Carbazóis/uso terapêuticoRESUMO
Retinal inflammation in a hyperglycemic condition is believed to play a crucial role in the development of diabetic retinopathy, and targeting inflammatory mediators is a promising strategy for the control of diabetic retinopathy. Curcumolide, a novel sesquiterpenoid with a unique 5/6/5 tricyclic skeleton, was isolated from Curcuma wenyujin. In this study, we demonstrate that treatment with curcumolide alleviated retinal inflammatory activities both in vitro and in vivo in a STZ-induced diabetic rat model and in TNF-α-stimulated HUVECs. Curcumolide alleviated retinal vascular permeability and leukostasis and attenuated the overexpression of TNF-α and ICAM-1 in diabetic retinas. Moreover, curcumolide also inhibited inducible p38 MAPK and NF-κB activation and the subsequent induction of proinflammatory mediators. These data suggest potential treatment strategies against diabetic retinopathy, particularly in the early stages of the disease.
