ROS1 is a validated therapeutic target in NSCLC. In a phase I study, the multitargeted MET proto-oncogene, receptor tyrosine kinase/anaplastic lymphoma kinase/ROS1 inhibitor crizotinib demonstrated ...remarkable efficacy in ROS1-rearranged NSCLCs and consequently gained approval by the United States Food and Drug Administration and by the European Medicines Agency in 2016. However, similar to other oncogene-driven lung cancers, ROS1-rearranged lung cancers treated with crizotinib eventually acquire resistance, leading to disease relapse. Novel ROS1 inhibitors and therapeutic strategies are therefore needed. Insights into the mechanisms of resistance to ROS1-directed tyrosine kinase inhibitors are now beginning to emerge and are helping to guide the development of new ROS1 inhibitors. This review discusses the biology and diagnosis of ROS1-rearranged NSCLC, and current and emerging treatment options for this disease. Future challenges in the field are highlighted.
Highlights • Individuals with asymptomatic malaria are an important reservoir of transmission. • Smear-positive asymptomatics are more infectious to mosquitoes than those with submicroscopic ...infection. • Current efforts to eliminate the malaria reservoir often target those with submicroscopic parasitemia. • The contribution of submicroscopic malaria to transmission needs further evaluation.
Abstract The health of the tens of millions of street children globally is understudied. We undertook a systematic review of the existing quantitative literature regarding the health status of street ...children and youth in low- and middle-income countries to summarize available knowledge, identify underexplored areas of research, and inform the future research agenda regarding the health of this population. A total of 108 articles met our inclusion criteria. Demographic data and structural factors associated with street life are summarized. Although data in specific regions or diseases are sparse, the literature review illustrates that youth's survival behaviors and the exposures associated with poor shelter have resulted in disproportionate morbidity in the areas of infectious illness, psychiatric disease, reproductive health, and perhaps to a lesser extent, growth. Vast areas of health that may disproportionately affect street children in childhood or later on as adults have not been investigated, including chronic diseases and cognitive deficits. Studies of specific diseases or conditions vary considerably by region. Strengths and limitations of the literature are discussed and principles for future research in this area are proposed.
For more than a decade, time series similarity search has been given a great deal of attention by data mining researchers. As a result, many time series representations and distance measures have ...been proposed. However, most existing work on time series similarity search relies on shape-based similarity matching. While some of the existing approaches work well for short time series data, they typically fail to produce satisfactory results when the sequence is long. For long sequences, it is more appropriate to consider the similarity based on the higher-level structures. In this work, we present a histogram-based representation for time series data, similar to the “bag of words” approach that is widely accepted by the text mining and information retrieval communities. We performed extensive experiments and show that our approach outperforms the leading existing methods in clustering, classification, and anomaly detection on dozens of real datasets. We further demonstrate that the representation allows rotation-invariant matching in shape datasets.
Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes ...in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and Methods We identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK resistance mutations and clinical outcomes on ALK TKIs were retrospectively evaluated according to ALK variant. A Foundation Medicine data set of 577 patients with ALK-positive NSCLC was also examined. Results The most frequent ALK variants were EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51 patients (40%). We analyzed 77 tumor biopsy specimens from patients with variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were significantly more common in variant 3 than in variant 1 (57% v 30%; P = .023). In particular, ALK G1202R was more common in variant 3 than in variant 1 (32% v 0%; P < .001). Analysis of the Foundation Medicine database revealed similar associations of variant 3 with ALK resistance mutation and with G1202R ( P = .010 and .015, respectively). Among patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival than variant 1 (hazard ratio, 0.31; 95% CI, 0.12 to 0.79; P = .011). Conclusion Specific ALK variants may be associated with the development of ALK resistance mutations, particularly G1202R, and provide a molecular link between variant and clinical outcome. ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors.
The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has ...demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of
mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions,
-ethyl-
-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single
mutations. In similar screens with EML4-ALK containing single
resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound
mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound
mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of
mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound
mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.
Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound
mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance.
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