Toshihiro Nukiwa

Tohoku University | Tohokudai · Department of Respiratory Medicine

IntroductionNintedanib is recommended for the treatment of idiopathic pulmonary fibrosis (IPF); however, treatment discontinuation due to adverse events (AEs) is common. A large-scale post-marketing surveillance study is investigating the real-world tolerability/safety of nintedanib in Japanese patients with IPF in routine clinical practice. Here,...

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO o...

Background Safety and pharmacokinetics (PK) of alpha1-proteinase inhibitor, modified process (Alpha-1 MP), was evaluated in a clinical trial of Japanese patients with alpha1-antitrypsin deficiency (AATD). The present study aimed to evaluate the long-term safety of weekly intravenous infusions of 60 mg/kg Alpha-1 MP in Japanese patients with AATD....

Background Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab...

9081 Background: NEJ009 study is the first randomized phase III trial that compared gefitinib plus chemotherapy with gefitinib in patients with untreated NSCLC harboring EGFR mutations. We report an updated OS and long-term tolerability analysis, including subgroup analyses focusing on a type of EGFR mutation and metastatic sites. Methods: Patients...

Background Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of fi...

Background Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease course. The recent advancement of antifibrotic therapy has increased the need for reliable and specific biomarkers. This study aimed to assess alveolar epithelial biomarkers as predictors for the efficacy of the antifibrotic drug pirfenidone. Me...

Background Thymic malignancies are a model of rare cancer. However, little clinical data is available based on the large database. We aimed to clarify the prognostic factors, particularly the metastatic sites, for thymic malignancies using one of the largest, representative, multi-institutional databases, the NEJ023 database. Patients and Methods...

Background: We investigated afatinib in elderly patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC). Patients and Methods: This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥ 75 years, with EGFR mutation-posit...

Background: Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of f...

9506 Background: In NEJ026, a phase III trial comparing bevacizumab plus erlotinib (BE) to erlotinib monotherapy (E) for EGFR-mutated non-small-cell lung cancer (NSCLC), we demonstrated the progression-free survival (PFS) of BE was significantly superior to E (Saito et al. Lancet Oncol. 2019 May;20(5):625-635.). However overall survival analysis we...

Background Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. Material and Methods We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative tr...

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor combined with cytotoxic chemotherapy is highly effective for the treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations; however, little is known about the efficacy and safety of this combination compared with that of standard therapy with EGFR- tyrosi...

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Background This prospective, post-marketing observational study in Japanese patients aimed to evaluate the safety and effectiveness of daily afatinib use in general practice. Methods This non-interventional study (NCT02131259) enrolled treatment-naïve and pre-treated patients with inoperable/recurrent EGFR mutation-positive NSCLC, eligible for afa...

Background: Resistance to first-generation or second-generation EGFR tyrosine kinase inhibitor (TKI) monotherapy develops in almost half of patients with EGFR-positive non-small-cell lung cancer (NSCLC) after 1 year of treatment. The JO25567 phase 2 trial comparing erlotinib plus bevacizumab combination therapy with erlotinib monotherapy establish...

Background Alpha1-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60 mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluat...

Background/aim: Promising reports have described the combination of first-generation epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) with carboplatin plus pemetrexed or bevacizumab. However, no analysis of afatinib with platinum-doublet chemotherapies has been performed. Patients and methods: We evaluated the safety and a...

Background: The prognostic factors and the efficacy of first-line chemotherapy remain unclear in patients with advanced thymic carcinoma. Materials and methods: We conducted a multi-institutional retrospective study named NEJ023 for patients with advanced thymic carcinoma. All patients without any indication of curative treatment were treated wi...

Background The North-East Japan Study Group (NEJ) 005/Tokyo Cooperative Oncology Group (TCOG) 0902 study has reported that first-line concurrent and sequential alternating combination therapies of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer...

Mast cells, basophils, and eosinophils are central effectors in allergic inflammatory disorders. These cells secrete abundant serine proteases as well as chemical mediators and cytokines; however, the expression profiles and functions of their endogenous inhibitors remain elusive. We found that murine secretory leukoprotease inhibitor (SLPI) is exp...

Objective Carboplatin-based regimens are the standard regimens for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, the efficacies of these regimens are unsatisfactory. We previously identified carboplatin plus irinotecan (CI) and carboplatin plus amrubicin (CA) as promising new carboplatin-based regimens. Accordingly, we co...

Objective The standard regimen of S-1 monotherapy, comprising 4 weeks of administration followed by 2 weeks of rest, frequently causes gastrointestinal toxicity. Studies indicate that alternate-day administration of S-1 decreases gastrointestinal toxicity in advanced gastric cancer. We conducted a randomized phase II trial among patients with previ...

Doc. S1. Additional detail on the methods. Fig. S1. Chest CT and brain MRI of subject 1 (an 80‐year‐old woman). Table S1. Sequencing read information and exome coverage statistics for each sample. Table S2. Exonic variants called in genomic DNA from peripheral blood. Table S3. Chromosome 1–5: candidate variants identified in all four patients,...

9038 Background: North East Japan Study Group (NEJ) 005/ Tokyo Cooperative Oncology Group (TCOG) 0902 study has demonstrated that first-line concurrent (C) and sequential alternating (S) combination therapies of EGFR tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with...

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte/macrophage colony stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid (BALF). The antibodies inhibit the maturati...

Lung cancer accompanied by somatic activating mutations in the epidermal growth factor receptor (EGFR) gene, which is associated with a significant clinical response to the targeted therapy, is frequently found in never-smoking Asian women with adenocarcinoma. Although this implies genetic factors underlying the carcinogenesis, the etiology remains...

Background and objective: Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia. Nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) compared with placebo in patients with IPF in two replicate trials (INPULSIS®). We examined the efficacy and safety of...

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Appendix

Influenza virus epidemics potentially cause pneumonia, which is responsible for much of the mortality due to the excessive immune responses. The role of costimulatory OX40-OX40 ligand (OX40L) interactions has been explored in the non-infectious pathology of influenza pneumonia. Here, we describe a critical contribution of OX40L to infectious pathol...

Introduction . Rebiopsies have become more crucial in non-small cell lung cancer (NSCLC). Instead of invasive biopsies, development of collecting biological data of the tumor from blood samples is expected. We conducted a prospective study to assess the feasibility of detection of epidermal growth factor receptor (EGFR) mutation in plasma samples....

Supplemental Figure. Mechanism of PNA-LNA Clamp PCR. Supplemental Table 1. Primers and probes listed by assay. Supplemental Table 2. PCR cycles.

Background: Second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib as first-line treatment has been demonstrated to improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC) harboring an exon 19 deletion (del19) of EGFR compared to platinum-doublet chemotherapy. However, it is uncle...

Background: A phase III clinical trial of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) in Japan has revealed that pirfenidone attenuated the decline in vital capacity (VC) and improved progression-free survival (PFS). We conducted an extended analysis of the pirfenidone trial to investigate its efficacy with respect to IPF seve...

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease with a median survival of 2-5 years and limited treatment options. In 2008, pirfenidone became the first drug to be approved for IPF treatment in Japan. The aim of this study was to assess the safety of pirfenidone for IPF treatment in a clinical setting. Methods:...

The use of lung progenitors for regenerative medicine appears promising, but their biology is not fully understood. Here, we found anti-inflammatory attributes in bronchiolar progenitors that were sorted as a multipotent subset of mouse club cells and found to express secretory leukocyte protease inhibitor (SLPI). Notably, the impaired expression o...

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a lifethreatening event and one of the important endpoints in clinical trials involving IPF. Despite this, there has been little evaluation of the potential risk factors for AE-IPF in clinical trials. We evaluated the risk factors for AE-IPF in a phase III clinical trial o...

We conducted a phase I dose escalation study to evaluate the feasibility, maximum tolerated dose (MTD), and recommended dose (RD) of weekly irinotecan combined with fixed-dose carboplatin for patients with untreated small-cell lung cancer (SCLC). Fifteen patients with chemotherapy-naïve SCLC less than 75 years old were enrolled from 3 institutions....

Amrubicin and re-challenge of platinum doublet are both effective treatments for sensitive-relapsed small-cell lung cancer (SCLC). However, no comparative study of these treatments has been reported. This randomized study was conducted to select the most suitable regimen for future evaluation. SCLC patients who had relapsed more than 90 days after...

Objective Epidermal growth factor receptor tyrosine kinase inhibitors are effective as first-line therapy for advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutations. However, it is unknown whether second-line platinum-based chemotherapy after epidermal growth factor receptor tyrosine kinase inhibitor thera...

There have been no prospective large-scale multicenter epidemiological studies on the clinical course and treatment from the time of diagnosis of idiopathic interstitial pneumonias (IIPs) in Japan. The purpose of this study was to clarify the current clinical situation of IIP in Japan. This study was supported by a grant from the Ministry of Health...

Background: The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III...

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment is the standard therapy for non-small cell lung cancer (NSCLC) harbouring EGFR-activating mutations. The NEJ002 phase 3 clinical trial demonstrated the efficacy of EGFR-TKI; gefitinib was significantly superior in both progression-free survival (PFS) and objective res...

Objective: To assess outcomes of elderly patients with advanced NSCLC harboring an EGFR mutation treated with gefitinib, as well as safety and impact on quality of life (QoL). Methods: We performed a retrospective analysis of pooled data from one Phase III and two Phase II studies of 71 patients aged ≥ 70 years with a performance status of 0 - 2...

Background: There has been no standard chemotherapy for advanced or recurrent thymic malignancies including thymic carcinoma (TC) and invasive thymoma (IT), though platinum and anthracycline have been reported as effective agents for the treatment of these diseases. The objective of this study was to evaluate the efficacy and safety of the combina...

EGFR is an important therapeutic target for non-small cell lung cancers (NSCLCs). Tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, are effective in cases with EGFR-activating mutations. However, most such cases become resistant through a secondary EGFR mutation, T790M. While the second-generation TKI afatinib has a higher affinit...

Current hypotheses suggest aberrant wound healing has a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In these hypotheses, continuous TGF-beta1 secretion by alveolar epithelial cells (AECs) in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells (M...

Chronic inflammation induces lymphangiogenesis and blood vessel remodeling. Since aged pneumonia patients often have repeated episodes of aspiration pneumonia, the pathogenesis may involve chronic inflammation. For lymphangiogenesis, VEGFR-3 and its ligand VEGF-C are key factors. No previous studies have examined chronic inflammation or vascular ch...

Background: The first-line combination of an EGFR-TKI plus platinum-based doublet chemotherapy has yet to be sufficiently evaluated for patients with EGFR-mutant NSCLC. This randomized phase II trial was designed to identify an effective combined regimen of gefitinib (G) plus carboplatin/pemetrexed (CP) for subsequent use in phase III study. Method...

Background Influenza virus infection-induced inflammatory responses are associated with fever and other symptoms. Although macrolide antibiotics (macrolides) provide anti-inflammatory effects, these effects have not been well studied in influenza patients. Methods We examined the effects of clarithromycin on influenza symptoms. A randomized, prosp...

Aim: When this trial was planned, A was believed to be a promising new anthracycline agent for sensitive-relapsed SCLC. While re-challenge of P that had been used for the first-line treatment was also believed to be effetive for sensitive-relapsed SCLC, although prospective evaluation of it had not been reported. Thus this randomized phase 2 study...

Aim: Cisplatin-based regimens are standard first-line chimotherapy for extensive-disease small -ell lung cancer (ED-SCLC). In patients (pts) unfit for cisplatin due to advanced age or poor performance status (PS), carboplatin plus etoposide (CE) is as effective as cisplatin plus etoposide (JCOG9702 trial), although its efficacy is not satisfactory....

Aim: The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) plus platinum-based doublet chemotherapy has yet to be sufficiently evaluated for patients with EGFR-mutant NSCLC. This randomized phase II study was designed to select the combination regimen for phase III evaluation. Methods: Chemotherapy...

The performance of scientifically and ethically valid prospective clinical trials is the only means by which to obtain reliable clinical evidence that can improve clinical practice and thus the outcome of patients with lung cancer. The efficacy of treatment for advanced lung cancer remains limited; many cooperative study groups for lung cancer have...

Background: Idiopathic interstitial pneumonias such as idiopathic pulmonary fibrosis or fibrotic nonspecific interstitial pneumonia are irreversible progressive pulmonary diseases that often have fatal outcomes. Although the etiology of idiopathic interstitial pneumonias is not yet fully understood, anti-fibrotic and anti-inflammatory agents have...

Small cell lung cancer (SCLC), approximately 15% of all the lung cancer cases, is a subtype of lung cancer with poor prognosis. Expression profiling analysis of 23 SCLC cases and 42 normal tissues revealed that EZH2 and other PRC2 members were highly expressed in SCLC. ChIP-seq analysis for H3K27me3 in 3 SCLC cell lines, Lu130, H209 and DMS53, show...

Background Amrubicin (AMR), a new anthracycline agent, has shown promising results for advanced small-cell lung cancer (SCLC), although the efficacy of AMR alone against refractory relapsed SCLC is insufficient. This study was conducted to evaluate the safety and efficacy of the combination of AMR and carboplatin (CBDCA) in patients with refractory...

Background: Standard first-line chemotherapy for elderly non-small cell lung cancer (NSCLC) patients has been monotherapy with vinorelbine or gemcitabine. Docetaxel has also been considered as an alternative option for the elderly population in Japan. We have previously demonstrated the high efficacy of carboplatin plus weekly paclitaxel for elder...

Objective Autoantibodies to aminoacyl-tRNA synthetases (ARSs) are useful in the diagnosis of idiopathic inflammatory myopathy (IIM) with interstitial pneumonia (IP). We developed an enzyme-linked immunosorbent assay (ELISA) system using a mixture of recombinant ARS antigens and tested its utility in a multicenter study. Methods: We prepared six rec...

A novel fusion gene that comprises the echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes was recently identified in non-small cell lung cancer (NSCLC), particularly in adenocarcinoma. A specific ALK inhibitor has been shown to exert anti-tumor effects in NSCLC with the EML4-ALK fusion gene. Previous...

Putative resident stem/progenitor cells have been identified in the bronchoalveolar duct junction (BADJ) of the murine lung. However, the contribution of stem cells expressing both Clara cell secretory protein (CCSP) and pro-surfactant protein C (SP-C) to the repair and maintenance of normal homeostasis is still unclear. In this study, we identifie...