Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves the overall survival of patients with
-mutated non-small-cell lung cancer (NSCLC). First-generation ...EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of
-mutated NSCLC, especially in patients with
exon 19 deletions or an exon 21 L858R mutation. However, almost all cases experience disease recurrence after 1 to 2 years due to acquired resistance. The
T790M mutation in exon 20 is the most frequent alteration associated with the development of acquired resistance. Osimertinib-a third-generation EGFR-TKI-targets the T790M mutation and has demonstrated high efficacy against
-mutated lung cancer. However, the development of acquired resistance to third-generation EGFR-TKI, involving the cysteine residue at codon 797 mutation, has been observed. Other mechanisms of acquired resistance include the activation of alternative pathways or downstream targets and histological transformation (i.e., epithelial⁻mesenchymal transition or conversion to small-cell lung cancer). Furthermore, the development of primary resistance through overexpression of the hepatocyte growth factor and suppression of Bcl-2-like protein 11 expression may lead to problems. In this report, we review these mechanisms and discuss therapeutic strategies to overcome resistance to EGFR-TKIs.
Adenosine is involved in a range of physiological and pathological effects through membrane-bound receptors linked to G proteins. There are four subtypes of adenosine receptors, described as A
AR, A
...AR, A
AR, and A
AR, which are the center of cAMP signal pathway-based drug development. Several types of agonists, partial agonists or antagonists, and allosteric substances have been synthesized from these receptors as new therapeutic drug candidates. Research efforts surrounding A
AR and A
AR are perhaps the most enticing because of their concentration and affinity; however, as a consequence of distressing conditions, both A
AR and A
AR levels might accumulate. This review focuses on the biological features of each adenosine receptor as the basis of ligand production and describes clinical studies of adenosine receptor-associated pharmaceuticals in human diseases.
Immune checkpoint inhibitors (ICI) are a novel medication for non-small cell lung cancer (NSCLC). Recent reports indicated that baseline tumor size (BTS) relates to the efficacy of ICI therapy for ...melanoma, but no study exists for NSCLC. This study aimed to evaluate the utility of BTS for ICI therapy.
Data from 58 patients diagnosed with NSCLC who underwent ICI monotherapy, were retrospectively analyzed. Patients were divided into two groups according to BTS (below 101 mm, above 101 mm). The primary endpoint was progression-free survival (PFS) and the secondary endpoint was overall survival (OS).
PFS of patients with a large BTS was significantly shorter than that of those with a small BTS (median; 2.07 95% confidence interval CI=0.99-6.77 months versus 6.39 95%CI=4.17-11.50 months) (p=0.044). OS of patients with large BTS was also significantly shorter (p<0.01).
BTS is a predictive and prognostic negative factor of ICI therapy for NSCLC.
Objective evaluations of cough frequency are considered important for assessing the clinical state of patients with respiratory diseases. However, cough monitors with audio recordings are rarely used ...in clinical settings. Issues regarding privacy and background noise with audio recordings are barriers to the wide use of these monitors; to solve these problems, we developed a novel automatic cough frequency monitoring system combining a triaxial accelerator and a stretchable strain sensor. Eleven healthy adult volunteers and 10 adult patients with cough were enrolled. The participants wore two devices for 30 min for the cough measurements. An accelerator was attached to the epigastric region, and a stretchable strain sensor was worn around their neck. When the subjects coughed, these devices displayed specific waveforms. The data from all the participants were categorized into a training dataset and a test dataset. Using a variational autoencoder, a machine learning algorithm with deep learning, the components of the test dataset were automatically judged as being a "cough unit" or "non-cough unit". The sensitivity and specificity in detecting coughs were 92% and 96%, respectively. Our cough monitoring system has the potential to be widely used in clinical settings without any concerns regarding privacy or background noise.
In recent years, multitarget drugs for neurological diseases such as Alzheimer's disease have been developed and well researched. Many studies have revealed that multitarget drugs are also useful for ...lung cancer and respiratory diseases. Pemetrexed is a multitargeted antifolate with strong antitumor activity against mesothelioma and lung adenocarcinoma. Crizotinib is an ATP-competitive tyrosine kinase inhibitor that targets
,
and
. Alectinib is known as an
inhibitor but also targets
,
,
,
and
. Sorafenib is a tyrosine kinase inhibitor that targets RAF kinase,
,
,
,
, and
. Nintedanib is a multiple tyrosine kinase inhibitor that targets
,
and
. In this review, we summarize the mechanisms of action of multitarget therapies and report the results of the latest clinical trials.
Nivolumab improves the survival of advanced non-small cell lung cancer (NSCLC), but a significant number of patients still fail to benefit from this treatment. In this study, we evaluated the ...efficacy of the time-series behavior of neutrophil-to-lymphocyte ratio (NLR) in a complete blood count from advanced NSCLC patients as a predictive marker of the anticancer effect of nivolumab.
We performed a retrospective review of medical records and collected data on patients with advanced NSCLC treated with nivolumab as second- and further-line treatments from December 2015 to March 2017. The NLRs were calculated before each treatment cycle for four cycles. These parameters were tested for its association with the overall survival (OS), progression-free survival (PFS) and time to treatment failure (TTF).
Nineteen patients were treated with nivolumab. Stratified by the response to nivolumab, the median OS was 2.8 months in progressive disease (PD) and 14.0 months in non-PD (p = 0.002). Before discontinuation of PD or toxicity, an NLR is rising from baseline in 5 out of 7 patients with PD and all of 4 patients with discontinuation due to toxicity. Patients with an >30% increase in NLR were associated with a significantly shorter TTF compared with those with stable or decrease in NLR both after first cycle (p = 0.014) and second cycle (p < 0.001).
The NLR is suggested to be useful not only as a prognostic marker but also as a predictive marker for treatment with nivolumab. Further prospective study is warranted to develop a predictive algorithm to detect PD cases as early as possible by focusing the time-series behavior of NLR.
Elucidating reaction inhomogeneity of composite electrodes is key to improve the performances of batteries such as rate capability and durability. Because the reaction inhomogeneity often disappears ...after a certain relaxation period, operando analytical techniques are indispensable. We hereby propose that operando optical analysis as a common lab method can be applied to visualize the reaction inhomogeneity of LiFePO4 composite electrodes for lithium-ion batteries with sufficient space and time resolutions. The results indicate that the brightness of the charged phase was higher than that of the discharged phases, which can be used to separate the phases and thus to elucidate the reaction inhomogeneity in the cross section of the composite electrode. A metastable phase Li3/4FePO4 was also captured at a low temperature with the optical analysis.
PDF
