Stress Response Kinase MK2 Induces Non-canonical Activation of EphA2 in EML4-ALK Lung Cancer Cells.

The non-canonical phosphorylation of the receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) at Ser-897 plays crucial roles in tumor progression in a tyrosine kinase-independent manner. This phosphorylation is catalyzed by p90 ribosomal S6 kinase (RSK), a kinase downstream of extracellular signal-regulated kinase (ERK). We recently reported that stress-responsive kinase mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), instead of ERK, regulates RSK under cellular stress conditions; however, the function of MK2 in ERK-activated cells is still unknown.

Five-year efficacy and safety of pembrolizumab as first-line treatment in patients with non-small cell lung cancer with PD-L1 tumor proportion score ≥50 %: A multicenter observational study.

Introduction: Use of pembrolizumab as first-line treatment in patients with non-small cell lung cancer (NSCLC) with PD-L1 tumor proportion score (TPS) ≥ 50 % was approved in Japan 5 years ago. We investigated the long-term efficacy and safety of this treatment in a real-world setting.

Methods: This multicenter observational study enrolled 95 consecutive cases of histologically diagnosed advanced or recurrent NSCLC with a PD-L1 TPS score ≥ 50 %, who received pembrolizumab as first-line treatment between February 2017 and December 2018.

Etiologies and Treatment Outcomes of Chronic Cough Diagnosed with a Pathophysiological Diagnostic Procedure: A Single-center Retrospective Observational Cohort Study.

Objective: We developed a pathophysiological diagnostic procedure to identify etiologies of chronic cough (CC) like cough variant asthma (CVA), atopic cough (AC), cough predominant asthma, sinobronchial syndrome (SBS), and mucoid impaction of small bronchi. After identifying the etiologies of CC through an understanding of its pathophysiological processes, we determined the patient's management outcomes based on the pathophysiological diagnosis.

Material And Methods: In this retrospective observational cohort study, the medical records of CC patients from April 2013 to March 2018 was analyzed to assess the etiologies and treatments based on the pathophysiological diagnostic procedure.

Successful osimertinib treatment for Meckel's cave metastasis: a case report.

Osimertinib has emerged as the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutations, offering improved tolerability and demonstrating superior efficacy against brain metastases in comparison with other tyrosine kinase inhibitors. The Meckel's cave is a dural recess in the posteromedial part of the middle cranial fossa that acts as a conduit for the trigeminal nerve between the anterior pontine cisterna and the cavernous sinus, and houses the Gasserian ganglion and proximal radicle of the trigeminal nerve. Trigeminal neuropathy, characterized by numbness and dysesthesia of the skin and mucous membranes of the face, poses diagnostic challenges and often requires differentiation from conditions, such as compression neuropathy, inflammation, and drug-induced reactions.

combined with L858R mutation reduced afatinib sensitivity and associated to early recurrence in lung cancer.

Background: The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is widely used as a first-line treatment for -mutated non-small cell lung cancer (NSCLC). However, there is no established treatment for osimertinib resistance, so second-generation afatinib is an alternative treatment option. The purpose of this study was to elucidate gene alterations associated with afatinib efficacy and resistance by analyzing cell-free DNA (cfDNA) obtained from patients with -mutated NSCLC.

Analysis of Methylation of Tumor-suppressive miRNAs and Mutations in Pancreatic Juice.

Background/aim: We previously reported the usefulness of detecting aberrant methylation in tumor suppressive microRNAs (miRNAs) in bile and plasma to discriminate pancreaticobiliary cancers from benign pancreaticobiliary diseases. This study analyzed the methylation of miRNAs in pancreatic juice to identify those specific to pancreatic cancer (PC).

Patients And Methods: Pancreatic juice was collected from 20 patients with PC, including eight with intraductal papillary mucinous carcinoma (IPMC), two with low grade-pancreatic intraepithelial neoplasia (LG-PanIN), 32 with LG-intraductal papillary mucinous neoplasm (IPMN), and seven with benign pancreatic lesions.

YAP regulates HER3 signaling-driven adaptive resistance to RET inhibitors in RET-aberrant cancer.

Purpose: Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKIs). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance.

Serum Inflammatory Dynamics as Novel Biomarkers for Immune Checkpoint Inhibitors in Non-small-cell Lung Cancer With Bone Metastases.

Background/aim: The aim of the study was to develop a novel predictive scoring system based on the dynamics of serum inflammatory indicators in immune checkpoint inhibitor (ICI) treatment on non-small-cell lung cancer (NSCLC) with bone metastases.

Patients And Methods: Sixty patients with NSCLC and bone metastases treated with ICIs between January 2016 and March 2021 were included in the development cohort. Serum neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) levels were assessed before (pre-value) and 6 weeks after (post-value) ICI treatment, and a novel predictive score was developed: pre-value ≥ post-value, 0 points; pre-value < post-value, 1 point; total score: 0-2 points.

Comprehensive antitumor immune response boosted by dual inhibition of SUMOylation and MEK in MYC-expressing KRAS-mutant cancers.

Precision medicine has drastically changed cancer treatment strategies including KRAS-mutant cancers which have been undruggable for decades. While intrinsic or acquired treatment resistance remains unresolved in many cases, epigenome-targeted therapy may be an option to overcome. We recently discovered the effectiveness of blocking small ubiquitin-like modifier (SUMO) signaling cascade (SUMOylation) in MYC-expressing KRAS-mutant cancer cells using a SUMO-activating enzyme E inhibitor TAK-981 that results in SUMOylation inhibition.

Triple combination therapy comprising osimertinib, an AXL inhibitor, and an FGFR inhibitor improves the efficacy of EGFR-mutated non-small cell lung cancer.

We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC.

The role of cytidine 5'-triphosphate synthetase 1 in metabolic rewiring during epithelial-to-mesenchymal transition in non-small-cell lung cancer.

Epithelial-to-mesenchymal transition (EMT) contributes to the poor prognosis of patients with cancer by promoting distant metastasis and anti-cancer drug resistance. Several distinct metabolic alterations have been identified as key EMT phenotypes. In the present study, we further characterize the role of transforming growth factor-β (TGF-β)-induced EMT in non-small-cell lung cancer.

Dual inhibition of SUMOylation and MEK conquers MYC-expressing KRAS-mutant cancers by accumulating DNA damage.

Background: KRAS mutations frequently occur in cancers, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Although KRAS inhibitors have recently been approved, effective precision therapies have not yet been established for all KRAS-mutant cancers. Many treatments for KRAS-mutant cancers, including epigenome-targeted drugs, are currently under investigation.

Prognostic value of coexisting conditions and complications in pleuroparenchymal fibroelastosis: a single-center retrospective study.

Background: Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial lung disease (ILD) characterized by subpleural parenchymal fibrosis and elastosis mainly in the upper lobes. PPFE occurs in a secondary form that overlaps with underlying medical conditions or complications. This study evaluated the clinical impact of coexisting factors on the survival of patients with PPFE.

Combination therapy with immune checkpoint inhibitors and denosumab improves clinical outcomes in non-small cell lung cancer with bone metastases.

Background: The concomitant use of denosumab and immune checkpoint inhibitor (ICI) treatment may have synergistic effects and enhance antitumor activity; however, this has not been fully evaluated. This study aimed to evaluate the clinical outcomes of non-small cell lung cancer (NSCLC) patients with bone metastases receiving combination therapy and to identify the best combination regimen.

Methods: Eighty-six NSCLC patients with bone metastases who received ICI treatment were enrolled in this study.

Combining dynamics of serum inflammatory and nutritional indicators as novel biomarkers in immune checkpoint inhibitor treatment of non-small-cell lung cancer with bone metastases.

Objectives: We aimed to investigate the association of the dynamics of serum inflammatory and nutritional indicators with immune checkpoint inhibitor (ICI) response in non-small-cell lung cancer (NSCLC) with bone metastases, and to develop a novel predictive scoring system based on these indicators.

Methods: Patients with NSCLC having bone metastases treated with ICIs were categorized as: the development cohort (January 2016 to March 2021, n = 60) and the validation cohort (April 2021 to June 2023, n = 40). Serum indicators of inflammation and nutrition such as C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), albumin, prognostic nutritional index (PNI) were investigated before and six weeks after ICI initiation.

Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis.

Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment.

Targeting WEE1 enhances the antitumor effect of KRAS-mutated non-small cell lung cancer harboring TP53 mutations.

The clinical development of Kirsten rat sarcoma virus (KRAS)-G12C inhibitors for the treatment of KRAS-mutant lung cancer is limited by the presence of co-mutations, intrinsic resistance, and the emergence of acquired resistance. Therefore, innovative strategies for enhancing apoptosis in KRAS-mutated non-small cell lung cancer (NSCLC) are urgently needed. Through CRISPR-Cas9 knockout screening using a library of 746 crRNAs and drug screening with a custom library of 432 compounds, we discover that WEE1 kinase inhibitors are potent enhancers of apoptosis, particularly in KRAS-mutant NSCLC cells harboring TP53 mutations.

Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: a Co-MET study.

Background: MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation.

Methods: The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2).

Patients with idiopathic pulmonary fibrosis and refractory cough have traction bronchiectasis and distorted airway architecture: a retrospective case review study.

Cough is a common and important sign/symptom in patients with idiopathic pulmonary fibrosis (IPF). However, there have been few reports focusing on cough, and the exact mechanisms for cough in patients with IPF have remained unclear. The objective of this study was to investigate the clinical features of IPF patients with refractory cough and to clarify mechanisms for cough in these patients.

Comparing region of interest selection and whole-field analysis for measurement of ciliary beat frequency in high-speed video analysis.

Background: Ciliary beat frequency (CBF) is crucial in mucociliary clearance. High-speed video analysis (HSVA) is commonly used to measure CBF but lacks standardization. We compared visual observation and computer-assisted calculation using fast Fourier transformation (FFT) in freshly collected bronchial ciliary epithelial cells and cultured cells.