The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15-55%) have EGFR-driven ...mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting the PD-1/PDL-1 axis are a new anti-cancer therapy for metastatic NSCLC. The anti-PD-1/PDL-1 ICIs showed promising efficacy (~30% response rate) and improved the survival of patients with metastatic NSCLC, but the role of anti-PD-1/PDL-1 ICIs for EGFR mutant NSCLC is not clear. YAP (yes-associated protein) is the main mediator of the Hippo pathway and has been identified as promoting cancer progression, drug resistance, and metastasis in NSCLC. Here, we review recent studies that examined the correlation between the EGFR, YAP pathways, and PD-L1 and demonstrate the mechanism by which EGFR and YAP regulate PD-L1 expression in human NSCLC. About 50% of EGFR mutant NSCLC patients acquire resistance to EGFR-TKIs without known targetable secondary mutations. Targeting YAP therapy is suggested as a potential treatment for NSCLC with acquired resistance to EGFR-TKIs. Future work should focus on the efficacy of YAP inhibitors in combination with immune checkpoint PD-L1/PD-1 blockade in EGFR mutant NSCLC without targetable resistant mutations.
Taiwan experienced two waves of imported infections with Coronavirus Disease 2019 (COVID-19). This study aimed at investigating the genomic variation of severe acute respiratory syndrome coronavirus ...2 (SARS-CoV-2) in Taiwan and compared their evolutionary trajectories with the global strains. We performed culture and full-genome sequencing of SARS-CoV-2 strains followed by phylogenetic analysis. A 382-nucleotides deletion in open reading frame 8 (ORF8) was found in a Taiwanese strain isolated from a patient on February 4, 2020 who had a travel history to Wuhan. Patients in the first wave also included several sporadic, local transmission cases. Genomes of 5 strains sequenced from clustered infections were classified into a new clade with ORF1ab-V378I mutation, in addition to 3 dominant clades ORF8-L84S, ORF3a-G251V and S-D614G. This highlighted clade also included some strains isolated from patients who had a travel history to Turkey and Iran. The second wave mostly resulted from patients who had a travel history to Europe and Americas. All Taiwanese viruses were classified into various clades. Genomic surveillance of SARS-CoV-2 in Taiwan revealed a new ORF8-deletion mutant and a virus clade that may be associated with infections in the Middle East, which contributed to a better understanding of the global SARS-CoV-2 transmission dynamics.
Background Afatinib is one of the standard treatments for patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, data on the use of afatinib in ...patients with poor performance status (PS greater than or equai to 2) are limited. This study aimed to retrospectively review the clinical outcomes and safety of afatinib treatment in EGFR-mutation-positive (EGFRm+) NSCLC patients with PS greater than or equai to 2. Methods The data for 62 patients who were treated at Linkou Chang Gung Memorial Hospital from January 2010 to August 2019 were retrospectively reviewed. Patients' clinicopathological features were obtained, and univariate and multivariate analyses were performed to identify possible prognostic factors. Data on adverse events were collected to evaluate general tolerance for afatinib therapy. Results Until February 2020, the objective response rate, disease control rate, median progression-free survival (PFS), and overall survival (OS) were 58.1% (36/62), 69.4% (43/62), 8.8 months, and 12.9 months, respectively. The absence of liver metastasis (PFS: p = 0.044; OS: p = 0.061) and good disease control (p < 0.001 for PFS and OS) were independent favorable prognostic factors for PFS and OS. Bone metastasis (p = 0.036) and dose modification (reduction/interruption, p = 0.021) were predictors of disease control. Conclusion Afatinib demonstrated acceptable efficacy and safety in the current cohort. This study provided evidence to support the use of afatinib as a first-line treatment in EGFRm+ NSCLC patients with poor PS. Keywords: Lung cancer, Afatinib, EGFR, TKI, Performance status
Excessive glutamate release has been linked to stress and many neurodegenerative diseases. Evidence indicates abnormalities of glutamatergic neurotransmission or glutamatergic dysfunction as playing ...an important role in the development of many major psychiatric disorders (e.g., schizophrenia, bipolar disorder, and major depressive disorder). Recently, ketamine, an
-methyl-d-aspartate antagonist, has been demonstrated to have promisingly rapid antidepressant efficacy for treatment-resistant depression. Many compounds that target the glutamate system have also become available that possess potential in the treatment of major psychiatric disorders. In this review, we update evidence from recent human studies that directly or indirectly measured glutamatergic neurotransmission and function in major psychiatric disorders using modalities such as magnetic resonance spectroscopy, positron emission tomography/single-photon emission computed tomography, and paired-pulse transcranial magnetic stimulation. The newer generation of antidepressants that target the glutamatergic system developed in human clinical studies is also reviewed.
Although tumour PD‐L1 (CD274) expression had been used as a predictive biomarker in checkpoint immunotherapy targeting the PD1/PD‐L1 axis in various cancers, the regulation of PD‐L1 (CD274) ...expression is unclear. Yes‐associated protein (YAP), an important oncogenic protein in Hippo signalling pathway, reportedly promotes cancer development. We investigated whether inhibition of YAP down‐regulates PD‐L1 (CD274) in human malignant pleural mesothelioma (MPM). Western blotting showed that 2 human MPM cell lines (H2052 and 211H) had increased PD‐L1 protein expression compared to H290, MS‐1 and H28 cells. In H2052 and 211H cells, PD‐L1 mRNA expression was significantly increased compared to other MPM cell lines; YAP knockdown by small interfering RNA decreased PD‐L1 protein and mRNA expression. Forced overexpression of the YAP gene increased PD‐L1 protein expression in H2452 cells. Chromatin immunoprecipitation (ChIP) assay showed the precipitation of PD‐L1 enhancer region encompassing 2 putative YAP‐TEAD‐binding sites in H2052 cells. We found that, in human MPM tissue microarray samples, YAP and PD‐L1 concurrently expressed in immunohistochemistry stain (n = 70, P < .05, chi‐square). We conclude that PD‐L1 is correlated with YAP expression, and inhibition of YAP down‐regulates PD‐L1 expression in human MPM. Further study of how YAP regulates PD‐L1 in MPM is warranted.
Aerobic exercise has been identified as an effective strategy for transiently enhancing inhibitory control, an ability to suppress irrelevant distractors while focusing on relevant information in ...facilitating the implementation of goal‐directed behavior. The purpose of this study was to employ a go/no‐go version of the redundant‐target task and event‐related potential to further determine whether inhibitory control at the perceptual and response levels as well as their underlying processing capacity and neuroelectric alterations are differentially affected by a single bout of aerobic exercise. Twenty‐seven young adults completed the redundant‐target task while electroencephalogram was recorded before and after one 20‐min bout of moderate‐intensity aerobic exercise and a sitting control condition on separate days in counterbalanced order. Although behavioral outcomes of mean‐level performance did not differ between intervention conditions, time‐related decreases in processing capacity for the faster responses were only observed following rest. Aerobic exercise resulted in maintained P3b amplitude from pretest to posttest for all trial types while decreased P3b amplitude from pretest to posttest during single‐target and redundant‐target trials was observed following rest. Further, the time‐related changes in P3b amplitude were positively correlated with improvements in task performance following exercise. These findings suggest that a short bout of aerobic exercise selectively counteracts the time‐related decrements in processing capacity as well as neuroelectric processing of attention and conflict suppression that contribute to behavioral outcomes of inhibitory control.
A single bout of aerobic exercise selectively counteracts time‐related decrements in general information processing efficiency measured by system factorial technology (SFT) as well as neuroelectric correlates (i.e., P3‐ERP) of conflict suppression but not response inhibition when both these processes are required in a novel inhibitory control task. Further, P3b amplitude and task performance changes after exercise are positively correlated. The significance of these findings lies in the identification of conflict suppression as the isolated sub‐process that can transiently benefit from exercise.
The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) afatinib improves survival in nonsmall cell lung cancer (NSCLC) patients with EGFR mutation. We analysed the outcome between ...EGFR mutation subtypes in a large afatinib‐treated cohort in which 516 EGFR‐mutated NSCLC patients receiving afatinib as front‐line treatment. EGFR uncommon mutations include exon 20 insertion, de novo T790M of high or low allele frequency (dT790MHAF/dT790MLAF), non‐T790M compound mutation and others, where EGFR exon 20 insertion and dT790MHAF were defined as type‐I and the rest as type‐II uncommon mutation. Four hundred and sixty‐one (89.3%) and 55 (10.7%) patients were common and uncommon mutation, respectively. Exon 20 insertion and dT790MHAF patients demonstrated a significantly shortened progression‐free survival (PFS) (2.6 and 4.1 months) compared to EGFR common mutation, dT790MLAF and other uncommon mutation patients (15.1, 27.0 and 18.4 months; P = 3 × 10−8). Type‐I uncommon mutation was an independent predictor of PFS (HR 4.46 95% CI, 2.60‐7.64; P < .001) and OS (HR 2.56 95% CI, 1.37‐4.75; P = .003). EGFR L858R patients demonstrated a significantly higher CNS progression (cause‐specific HR, 3.16; 95% CI 1.24‐8.08; P = .016), and type‐I uncommon mutation patients exhibited a significantly higher systemic progression (cause‐specific HR, 4.95; 95% CI 2.30‐10.60; P = 4.3 × 10−5). Tendencies of higher CNS and lower systemic progression were observed in type‐II uncommon mutation patients. A PFS ≥ 12 months (OR 2.38 95% CI, 1.18‐4.89; P = .016) and uncommon EGFR mutation (OR 0.08 95% CI, 0.01‐0.48; P = .021) were independent predictors of secondary T790M. Afatinib‐treated NSCLC patients presented an EGFR genotype‐specific pattern of disease progression and outcome.
What's new?
For patients with nonsmall cell lung cancer (NSCLC), epidermal growth factor tyrosine kinase inhibitors (EGFR‐TKIs) can significantly improve survival. EGFG‐TKI effectiveness, however, is compromised by acquired EGFR mutations, especially de novo T790M mutations. Here, the impact of EGFR genotypes on the efficacy of afatinib, a second‐generation EGFR‐TKI, was investigated in a cohort of EGFR‐mutated NSCLC patients. Afatinib efficacy was associated with T790M allele quantity in patients with de novo T790M mutation. In particular, front‐line afatinib therapy was associated with favourable survival in EGFR‐mutated patients, whereas resistance was marked by a genotype‐specific pattern of disease progression, with secondary T790M development.
Final overall survival (OS) and time on treatment analysis of patients with
mutation-positive non-small-cell lung cancer (NSCLC) who received sequential afatinib and osimertinib.
Patients (n = 203) ...had T790M-positive disease following first-line afatinib and started osimertinib treatment ≥10 months before data entry. Primary outcome was time on treatment; OS analysis was exploratory.
Median time on treatment with afatinib and osimertinib was 27.7 months (90% CI: 26.7-29.9). Median OS was 37.6 months (90% CI: 35.5-41.3); median OS was 41.6 and 44.8 months in Del19-positive patients and Asian patients, respectively.
In real-world clinical practice, sequential afatinib and osimertinib was associated with encouraging outcomes in patients with
mutation-positive NSCLC, especially in Del19-positive patients and Asian patients.
NCT03370770 (ClinicalTrials.gov).
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