Hideyasu Yamada

University of Tsukuba · School of Medicine

Background/aim: Immune checkpoint inhibitors (ICIs) have revolutionized advanced non-small cell lung cancer (NSCLC) treatment. Even patients with epidermal growth factor receptor (EGFR)-mutated NSCLC may choose an ICI after failure of EGFR-tyrosine kinase inhibitor treatment. ICI-mediated immune-related adverse events (irAEs) may prompt NSCLC pati...

Background: The benefit of prompt vs delayed treatment initiation with inhaled long-acting bronchodilators in reducing exacerbations in chronic obstructive pulmonary disease (COPD) is unclear. This study aimed to investigate if long-acting bronchodilator therapy initiation within 30 days of COPD diagnosis reduces exacerbation risk in patients with...

Background: In recent years, several new biologics, such as benralizumab, have been developed to treat patients suffering from asthma poorly controlled by high-dose inhaled corticosteroids (ICS) and long-acting bronchodilators. Benralizumab is a humanized, interleukin (IL)-5Rα-specific monoclonal antibody that effectively ameliorates asthmatic epi...

Background: The benefit of prompt vs delayed treatment initiation with inhaled long-acting bronchodilators in reducing exacerbations in chronic obstructive pulmonary disease (COPD) is unclear. This study aimed to investigate if long-acting bronchodilator therapy initiation within 30 days of COPD diagnosis reduces exacerbation risk in patients with...

Background/aim: Real-world data on the clinical outcomes of first-line osimertinib treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations is lacking. This study aimed to reveal the treatment outcomes and prognostic factors of osimertinib as first-line therapy in clinical practice settings. Patients...

Background: Real-world data on the clinical outcomes of first-line osimertinib treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations is lacking. This study aimed to evaluate the treatment outcomes and the prognostic factors of osimertinib as first-line therapy in clinical practice settings. Methods:...

Purpose To characterize the clinical phenotypes of severe eosinophilic asthma based on early responsiveness to benralizumab in terms of forced expiratory volume in 1 second (FEV 1) improvement. Patients and methods Sixty-four participants diagnosed with severe eosinophilic asthma and who had completed 4 months of benralizumab treatment were include...

Purpose To characterize the clinical phenotypes of severe eosinophilic asthma based on early responsiveness to benralizumab in terms of forced expiratory volume in 1 second (FEV1) improvement. Patients and methods Sixty-four participants diagnosed with severe eosinophilic asthma and who had completed 4 months of benralizumab treatment were include...

Background/aim: To describe real clinical outcomes in patients with non-small cell lung cancer who have uncommon epidermal growth factor receptor (EGFR) mutations. Materials and methods: We performed a retrospective chart review from 15 medical institutes that cover a population of three million people from April 2008 to March 2019. Results: T...

This is the first study to perform comprehensive transcriptome analysis of whole blood cells to identify molecular phenotypes of severe eosinophilic asthma that correlate with responsiveness to benralizumab.

Aim: To clarify the correlation between serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) and metastasis and survival in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients. Patients and methods: CEA and CYFRA levels in 131 ALK-rearranged NSCLC patients were determined using fl...

Aim: To clarify the clinicopathological features in elderly anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) patients. Patients and methods: A retrospective study was performed in 129 ALK rearranged NSCLC patients diagnosed between April 2008 and March 2019 in fifteen Institutions of the Ibaraki prefecture, Japan....

Background: In the majority of non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations, first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are ineffective. The second-generation TKI, afatinib, is considered effective in patients with uncommon mutations, however, long-term survivors have been r...

Background/aim: Pleomorphic carcinoma of the lung is a rare, highly malignant subtype of lung cancer, with a more aggressive clinical course compared with other types of non-small-cell lung cancer (NSCLC). Platinum-containing chemotherapy has been the standard therapy for patients with NSCLC and pembrolizumab is one of the novel and reliable agent...

Background An orosomucoid-like 3 (ORMDL3)/gasdermin B (GSDMB) gene locus on chromosome 17q is consistently associated with childhood-onset asthma, which is highly atopic. As some evidence suggests the relationship between asthma and allergic sensitization reflects asthma patient susceptibility to augmented IgE responses driven by common environment...

Background/aim: To describe real clinical outcomes when using systemic therapy to treat non-small cell lung cancer (NSCLC) patients who have anaplastic lymphoma kinase (ALK) fusion gene mutation. Patients and methods: We performed a retrospective chart review from April 2008 to March 2019 sourced from 16 medical institutes that cover a populatio...

A 75‐year‐old woman presented with relapse a large mass in the left upper lobe of the lung (Figure 1‐A). Nine years earlier, the patient underwent a lobectomy of the left lower lung and mediastinal lymph node dissection due to a lung adenosqaumous cell carcinoma. The tumor was staged as pT3bN1M1a. An epidermal growth factor receptor (EGFR) exon 19...

A weighted genetic risk score (GRS) based on 16 SNPs implicated in reduced lung function in both Japanese and non-Japanese populations was previously associated with the onset of COPD and asthma. We here examine the genetic impact of this lung function GRS on specific COPD phenotypes. A cohort of Japanese COPD patients (N = 270) underwent lung func...

Background/aim: In patients with lung cancer, there has been no study that treated 'distant metastases' as 'metastatic patterns'. This study aimed to evaluate if specific 'metastatic patterns' exist in lung cancer patients. Patients and methods: Data were collected from lung cancer patients between 2009 and 2018. Metastatic patterns were analyze...

Background/aim: Distant organ metastases do not occur at random in lung cancer. A retrospective study was conducted in order to evaluate 1) what kinds of metastatic patterns exist in three different types of lung cancer, and 2) whether metastatic patterns affected prognosis in the different types of lung cancer. Patients and methods: Data were c...

Background In patients with bronchial asthma and those with chronic obstructive pulmonary disease (COPD), inhalation therapy and rinsing of the mouth and the oropharynx by gargling (“RMOG”) after inhalation are recommended. We performed a cross‐sectional audit aimed at investigating (a) the proportion of patients performing “RMOG” after inhalation...

Background A large body of evidence suggests that long-acting β2-adrenoceptor agonist (LABA)/long-acting muscarinic antagonist (LAMA) combinations induce a strong synergistic bronchodilatory effect in human isolated airways. Moreover, a recent post hoc analysis demonstrated clinical synergism between LABAs and LAMAs, which induces a synergistic imp...

Lung cancer is a major health concern worldwide, but new immunotherapeutic treatments for lung cancer have shown great promise and the prognosis for many severe cancers including lung cancer has been improving. In May 2017, the Food and Drug Administration approved pembrolizumab, a therapeutic antibody that blocks lymphocytic programmed death-1 (PD...

Background: TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activatio...

Aim: To describe the prevalence and determinants of acquired epidermal growth factor receptor (EGFR) T790M gene mutation in a clinical practice setting. Materials and methods: We performed a retrospective chart review study between January 2013 and November 2017 across multiple institutes, covering a population of 3 million people. Results: We...

Background Aldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascula...

Key Clinical Message We report the case of a 25‐year‐old woman with a pulmonary artery sling who was misdiagnosed as having childhood‐onset refractory asthma for approximately 20 years. The use of computed tomography may be useful for diagnosing this rare condition.

Background: Recent studies have demonstrated that a coding SNP (rs6967330, Cys529→Tyr) in cadherin-related family member 3 (CDHR3), which was previously associated with wheezing illness and hospitalizations in infancy, could support efficient human rhinovirus C (RV-C) entry and replication. Here, we sought to examine the genetic contribution of th...

Although our previous GWAS failed to identify SNPs associated with pulmonary function at the level of genomewide significance, it did show that the heritability for FEV1/FVC was 41.6% in a Japanese population, suggesting that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs. In addition,...

Susceptibility genes to pulmonary function traits in previous 6 GWASs. (DOCX)

Sixteen genes associated with FEV1/FVC in previous GWASs are nominally replicated in Japanese. (DOCX)

Differences in the GRS among the given asthma clusters according to the number of clusters. When k-means cluster analysis was repeated for the number of clusters (k) 3, 4, 5, 6, or 7, the maximum difference in the GRS among the k asthma clusters was obtained for k = 5 (ANOVA F = 4.8, P < 0.001). (TIF)

Characteristics of the asthma clusters. (DOCX)

Histogram of genetic risk scores (GRS) in healthy Japanese individuals. GRS in nonasthmatic, non-COPD healthy individuals of the Tsukuba cohort (N = 1364). The solid line indicates normal distribution. (TIF)

Functionally connected genes in GRAIL. (DOCX)

Top 20 pathways implicated by MetaCore™. (DOCX)

Correlation between genetic risk score and FEV1/FVC or annual decline in FEV1 in healthy individuals. FEV1/FVC (a) or annual decline in FEV1 (b). Linear approximation is shown by the fine black line (a). (TIF)

Demographic characteristics of the study cohorts. (DOCX)

Association between GRS (by 15 SNPs) and asthma. (DOCX)

Association between genetic risk score and asthma clusters. (DOCX)

Background: Long-acting β2-agonists (LABA) and leukotriene receptor antagonists (LTRA) are two principal agents that can be added to inhaled corticosteroids (ICS) for patients with asthma that is not adequately controlled by ICS alone. In our previous study, the Gly16Arg genotype of the β2-adrenergic receptor (ADRB2) gene did not influence the dif...

Aim: To elucidate the characteristics of patients with asthma who have specific IgE responses to inhaled allergens detected by ImmunoCAP, which is not detectable by MAST-26. Methods: A total of 168 patients with adult asthma who reside in the Kanto region were recruited. Levels of total serum IgE and allergen specific IgE antibodies towards 14 c...

Pulmonary function is a heritable trait, and recent genome-wide association studies (GWASs) have identified a number of loci influencing the trait. Genome-wide Complex Trait Analysis (GCTA) is a novel method provided by a software package that estimates the total additive genetic influence caused by common single nucleotide polymorphisms (SNPs) on...

Background It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments...

Introduction: We have previously reported that a distinct sensitization pattern was associated with thymic stromal lymphopoietin (TSLP) genotype. The aim of this study is to identify the characteristics of asthma phenotypes determined by a cluster analysis of IgE responsiveness and the relationship between these phenotypes and TSLP genotypes. Pat...

Most of the previously reported loci for total immunoglobulin E (IgE) levels are related to Th2 cell-dependent pathways. We undertook a genome-wide association study (GWAS) to identify genetic loci responsible for IgE regulation. A total of 479,940 single nucleotide polymorphisms (SNPs) were tested for association with total serum IgE levels in 118...

Recently, several genes and genetic loci associated with both asthma and chronic obstructive pulmonary disease (COPD) have been described as common susceptibility factors for the two diseases. In complex diseases such as asthma and COPD, a large number of molecular and cellular components may interact through complex networks involving gene-gene an...

Background: Cluster analyses were previously performed to identify asthma phenotypes underlying asthma syndrome. Although a large number of patients with asthma develop the disease later in life, these previous cluster analyses focused mainly patients with younger-onset asthma. Methods: Cluster analysis examined the existence of distinct phenoty...

Background: Atopy is a phenotypically heterogeneous condition, and the extent to which atopy accounts for asthma is controversial. In this study, we aimed to identify the presence of distinct sensitization patterns to common inhaled allergens and their association with asthma, allergic rhinitis and TSLP genotypes. Methods: We studied 1683 adults...

A 54-year-old woman complaining of muscle weakness and weight loss was admitted to our hospital with suspected polymyositis. Muscle biopsy revealed Langhans-type giant cells and noncaseating granulomas. Therefore, sarcoid myositis was diagnosed. The patient was treated with prednisolone, and the symptoms improved gradually. Generally, sarcoidosis i...