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1.
BMC Pulm Med ; 24(1): 511, 2024 Oct 14.
Article in English | MEDLINE | ID: mdl-39396941

ABSTRACT

BACKGROUND: Multidisciplinary discussion (MDD), in which physicians, radiologists, and pathologists communicate and diagnose together, has been reported to improve diagnostic accuracy compared to diagnoses made solely by physicians. However, even among experts, diagnostic concordance of MDD is not always good, and some patients may not receive a specific diagnosis due to insufficient findings. A provisional diagnosis based on the ontology with a diagnostic confidence level has recently been proposed. Additionally, we developed an artificial intelligence model to differentiate idiopathic pulmonary fibrosis (IPF) from other chronic interstitial lung diseases (ILD)s, which needs validation in a broader population. METHODS: This prospective nationwide ILD registry has recruited patients with newly diagnosed ILD at the referral respiratory hospitals in Japan and provides rapid MDD diagnoses and treatment recommendations through a central online MDD platform with a 3-year follow-up period. A modified diagnostic ontology is used. If no diagnosis reaches more than 50% certainty, the diagnosis is unclassifiable ILD. If multiple diseases are expected, the diagnosis with a high probability takes precedence. If the confidence levels for the top two possible diagnoses are equal, the diagnosis can be unclassifiable. The registry uses tentative diagnostic criteria for nonspecific interstitial pneumonia with organising pneumonia and smoking-related ILD not otherwise specified as possible new entities. Central MDD diagnosticians review the clinical data, test results, radiology images, and pathological specimens on a dedicated website and conduct MDD diagnoses using online meetings with a cloud-based reporting system. This study aims to (1) provide MDD diagnoses with treatment recommendations; (2) determine the overall ILD rates in Japan; (3) clarify the reasons for unclassifiable ILDs; (4) evaluate possible new disease entities; (5) identify progressive phenotypes and create a clinical prediction model; (6) measure the agreement rate between institutional and central diagnoses in ILD referral and non-referral centres; (7) identify key factors for each specific ILD diagnosis; and (8) create a new disease classification system based on treatment strategies, including the use of antifibrotic drugs. DISCUSSION: This study will provide ILD frequencies, including new entities, using central MDD on dedicated online systems, and develop a machine learning model for ILD diagnosis and prognosis prediction. TRIAL REGISTRATION: UMIN-CTR Clinical Trial Registry (UMIN000040678).


Subject(s)
Lung Diseases, Interstitial , Registries , Humans , Lung Diseases, Interstitial/diagnosis , Japan , Prospective Studies , Interdisciplinary Communication , Idiopathic Pulmonary Fibrosis/diagnosis , Diagnosis, Differential , Research Design
2.
BMC Pulm Med ; 23(1): 487, 2023 Dec 05.
Article in English | MEDLINE | ID: mdl-38053068

ABSTRACT

BACKGROUND: Human rhinoviruses (HRVs) infection is a common cause of exacerbations in pediatric patients with asthma. However, the effects of corticosteroids on HRV-induced exacerbations in pediatric asthma are unknown. We conducted a prospective observational study to determine the viral pathogens in school-age pediatric inpatients with asthma exacerbations. We assessed the effects of maintenance inhaled corticosteroids (ICS) on the detection rates of HRV species and treatment periods of systemic corticosteroids during exacerbations on pulmonary lung function after exacerbations. METHODS: Nasopharyngeal samples and clinical information were collected from 59 patients with asthma exacerbations between April 2018 and March 2020. Pulmonary function tests were carried out 3 months after exacerbations in 18 HRV-positive patients. Changes in forced expiratory volume in 1 second (FEV1)% predicted from baseline in a stable state were compared according to the treatment periods of systemic corticosteroids. RESULTS: Fifty-four samples collected from hospitalized patients were analyzed, and viral pathogens were identified in 45 patients (83.3%) using multiplex PCR assay. HRV-A, -B, and -C were detected in 16 (29.6%), one (1.9%), and 16 (29.6%) patients, respectively. The detection rates of HRV-C were lower in the ICS-treated group compared with those in the ICS-untreated group (p = 0.01), whereas maintenance ICS treatment did not affect the detection rate for viral pathogens in total and HRV-A. Changes in FEV1% predicted in patients treated with systemic corticosteroids for 6-8 days (n = 10; median, 4.90%) were higher than those in patients treated for 3-5 days (n = 8; median, - 10.25%) (p = 0.0085). CONCLUSIONS: Maintenance ICS reduced the detection rates of HRV (mainly HRV-C) in school-age inpatients with asthma exacerbations, and the treatment periods of systemic corticosteroids during exacerbations affected lung function after HRV-induced exacerbations. The protective effects of corticosteroids on virus-induced asthma exacerbations may be dependent upon the types of viral pathogen.


Subject(s)
Anti-Asthmatic Agents , Asthma , Child , Humans , Anti-Asthmatic Agents/therapeutic use , Rhinovirus , Inpatients , Administration, Inhalation , Asthma/drug therapy , Asthma/chemically induced , Adrenal Cortex Hormones
3.
Eur Respir J ; 60(6)2022 12.
Article in English | MEDLINE | ID: mdl-35361630

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease implicated as an independent risk factor for lung cancer. However, optimal treatment for advanced lung cancer with IPF remains to be established. We performed a randomised phase 3 trial (J-SONIC) to assess the efficacy and safety of nintedanib plus chemotherapy (experimental arm) compared with chemotherapy alone (standard-of-care arm) for advanced nonsmall cell lung cancer (NSCLC) with IPF. METHODS: Chemotherapy-naĆÆve advanced NSCLC patients with IPF were allocated to receive carboplatin (area under the curve of 6 on day 1) plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) (100Ć¢Ā€Ā…mgĀ·m-2 on days 1, 8 and 15) every 3Ć¢Ā€Ā…weeks with or without nintedanib (150Ć¢Ā€Ā…mg twice daily, daily). The primary end-point was exacerbation-free survival (EFS). RESULTS: Between May 2017 and February 2020, 243 patients were enrolled. Median EFS was 14.6Ć¢Ā€Ā…months in the nintedanib plus chemotherapy group and 11.8Ć¢Ā€Ā…months in the chemotherapy group (hazard ratio (HR) 0.89, 90% CI 0.67-1.17; p=0.24), whereas median progression-free survival was 6.2 and 5.5Ć¢Ā€Ā…months, respectively (HR 0.68, 95% CI 0.50-0.92). Overall survival was improved by nintedanib in patients with nonsquamous histology (HR 0.61, 95% CI 0.40-0.93) and in those at GAP (gender-age-physiology) stage I (HR 0.61, 95% CI 0.38-0.98). Seven (2.9%) out of 240 patients experienced acute exacerbation during study treatment. CONCLUSIONS: The primary end-point of the study was not met. However, carboplatin plus nab-paclitaxel was found to be effective and tolerable in advanced NSCLC patients with IPF. Moreover, nintedanib in combination with such chemotherapy improved overall survival in patients with nonsquamous histology.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , Idiopathic Pulmonary Fibrosis , Lung Neoplasms , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/drug therapy , Idiopathic Pulmonary Fibrosis/complications , Idiopathic Pulmonary Fibrosis/drug therapy , Lung Neoplasms/complications , Lung Neoplasms/drug therapy , Paclitaxel , Male , Female
4.
BMC Cancer ; 22(1): 503, 2022 May 06.
Article in English | MEDLINE | ID: mdl-35524214

ABSTRACT

BACKGROUND: Many studies have recently reported the association of concomitant medications with the response and survival in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy. However, the clinical impact of statin therapy on the outcome of cancer immunotherapy in patients with NSCLC is poorly understood. METHODS: In our database, we retrospectively identified and enrolled 390 patients with advanced or recurrent NSCLC who were treated with anti-programmed cell death-1 (PD-1) monotherapy in clinical practice between January 2016 and December 2019 at 3 medical centers in Japan to examine the clinical impact of statin therapy on the survival of patients with NSCLC receiving anti-PD-1 monotherapy. A propensity score-matched analysis was conducted to minimize the bias arising from the patients' backgrounds. RESULTS: The Kaplan-Meier curves of the propensity score-matched cohort showed that the overall survival (OS), but not the progression-free survival (PFS), was significantly longer in patients receiving statin therapy. However, a Cox regression analysis in the propensity score-matched cohort revealed that statin therapy was not an independent favorable prognostic factor, although it tended to be correlated with a favorable outcome. CONCLUSIONS: Statin therapy may be a combination tool for cancer immunotherapy in patients with NSCLC. These findings should be validated in further prospective studies with larger sample sizes.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Lung Neoplasms , Antibodies, Monoclonal, Humanized , Carcinoma, Non-Small-Cell Lung/drug therapy , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Propensity Score , Prospective Studies , Retrospective Studies
5.
Molecules ; 27(12)2022 Jun 08.
Article in English | MEDLINE | ID: mdl-35744816

ABSTRACT

Molybdenum (Mo) is an essential trace element in all kingdoms of life. Mo is bioavailable as the oxyanion molybdate and gains biological activity in eukaryotes when bound to molybdopterin, forming the molybdenum cofactor. The imbalance of molybdate homeostasis results in growth deficiencies or toxic symptoms within plants, fungi and animals. Recently, fluorescence resonance energy transfer (FRET) methods have emerged, monitoring cellular and subcellular molybdate distribution dynamics using a genetically encoded molybdate-specific FRET nanosensor, named MolyProbe. Here, we show that the MolyProbe system is a fast and reliable in vitro assay for quantitative molybdate determination. We added a Strep-TagII affinity tag to the MolyProbe protein for quick and easy purification. This MolyProbe is highly stable, resistant to freezing and can be stored for several weeks at 4 Ā°C. Furthermore, the molybdate sensitivity of the assay peaked at low nM levels. Additionally, The MolyProbe was applied in vitro for quantitative molybdate determination in cell extracts of the plant Arabidopsis thaliana, the fungus Neurospora crassa and the yeast Saccharomyces cerevisiae. Our results show the functionality of the Arabidopsis thaliana molybdate transporter MOT1.1 and indicate that FRET-based molybdate detection is an excellent tool for measuring bioavailable Mo.


Subject(s)
Arabidopsis , Anion Transport Proteins , Arabidopsis/metabolism , Arabidopsis Proteins , Fluorescence Resonance Energy Transfer , Molybdenum/metabolism , Neurospora crassa , Saccharomyces cerevisiae/metabolism
6.
Int J Cancer ; 149(2): 473-482, 2021 07 15.
Article in English | MEDLINE | ID: mdl-33720422

ABSTRACT

The gastrointestinal microbiota was reported as an important factor for the response to cancer immunotherapy. Probiotics associated with gastrointestinal dysbiosis and bacterial richness may affect the efficacy of cancer immunotherapy drugs. However, the clinical impact of probiotics on the efficacy of cancer immunotherapy in patients with nonsmall cell lung cancer (NSCLC) is poorly understood. The outcomes of 294 patients with advanced or recurrent NSCLC who received antiprogrammed cell death-1 (PD-1) therapy (nivolumab or pembrolizumab monotherapy) at three medical centers in Japan were analyzed in our study. We used inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients' backgrounds. The IPTW-adjusted Kaplan-Meier curves showed that progression-free survival (nonuse vs use: hazard ratio [HR] [95% confidence interval {CI}]Ā =Ā 1.73 [1.42-2.11], log-rank test PĀ =Ā .0229), but not overall survival (nonuse vs use: HR [95%CI]Ā =Ā 1.40 [1.13-1.74], log-rank test PĀ =Ā .1835), was significantly longer in patients who received probiotics. Moreover, the IPTW-adjusted univariate analyses showed that nonuse or use of probiotics was significantly associated with disease control (nonuse vs use: odds ratio [OR] [95%CI]Ā =Ā 0.51 [0.35-0.74], PĀ =Ā .0004) and overall response (nonuse vs use: OR [95%CI]Ā =Ā 0.43 [0.29-0.63], P < .0001). In this multicenter and retrospective study, probiotics use was associated with favorable clinical outcomes in patients with advanced or recurrent NSCLC who received anti-PD-1 monotherapy. The findings should be validated in a future prospective study.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/administration & dosage , Lung Neoplasms/drug therapy , Probiotics/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , B7-H1 Antigen/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Drug Synergism , Female , Gastrointestinal Microbiome/drug effects , Humans , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/genetics , Male , Mutation , Neoplasm Recurrence, Local , Nivolumab/administration & dosage , Nivolumab/therapeutic use , Probiotics/pharmacology , Prospective Studies , Retrospective Studies , Survival Analysis , Treatment Outcome
7.
Cancer Sci ; 112(11): 4692-4701, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34431585

ABSTRACT

Postmarketing surveillance of Japanese patients with unresectable, previously treated, advanced or recurrent non-small-cell lung cancer treated with nivolumab was undertaken during the conditional approval period. The study aim was to evaluate the occurrence of treatment-related adverse events of nivolumab in the real world. Patients were registered between December 2015 and March 2016 at 536 sites. Nivolumab was given intravenously (3Ā mg/kg every 2Ā weeks); the observation period was 12Ā months after the first dose of nivolumab. Patients were evaluated for safety (nĀ =Ā 3601; 18.2% ≥75Ā years, 22.4% ECOG performance statusĀ ≥2) and effectiveness (nĀ =Ā 3570). The frequencies of any grade and grade 3 or higher treatment-related adverse events were 47.1% and 15.9%, respectively. The most frequent treatment-related adverse events (any grade) were interstitial lung disease (6.4%), hypothyroidism (5.7%), and diarrhea (4.4%). Treatment-related adverse events of special interest (priority items) occurring at a frequency of 5% or more were adverse events related to interstitial lung disease, thyroid dysfunction, liver dysfunction, colitis/severe diarrhea, infusion reaction, and infusion reaction within 24Ā hours. Significant risk factors for these priority items were identified by competing risk analysis: interstitial lung disease (previous/comorbid interstitial lung disease, abnormal findings on chest imaging, and smoking history); liver dysfunction (previous/comorbid liver disease, smoking history, and metastasis); thyroid dysfunction (previous/comorbid thyroid disease and performance status); and colitis/severe diarrhea (treatment line 2 vs ≥3). The 12-month survival rate was 40.7%. In conclusion, the safety profile of nivolumab in this postmarketing surveillance was similar to that in clinical trials, and no new safety signals were identified. The study was registered with the Japan Pharmaceutical Information Center (clinicaltrials.jp: Japic-163271).


Subject(s)
Antineoplastic Agents, Immunological/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Nivolumab/adverse effects , Product Surveillance, Postmarketing , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/administration & dosage , Carcinoma, Non-Small-Cell Lung/mortality , Diarrhea/chemically induced , Drug Administration Schedule , Female , Humans , Hypothyroidism/chemically induced , Japan , Lung Diseases, Interstitial/chemically induced , Lung Neoplasms/mortality , Male , Middle Aged , Nivolumab/administration & dosage , Prospective Studies , Risk Factors , Smoking/adverse effects , Survival Rate
8.
Int Immunol ; 32(8): 547-557, 2020 07 28.
Article in English | MEDLINE | ID: mdl-32253426

ABSTRACT

Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes and are becoming a standard treatment for many cancer types. However, these drugs also induce immune-related adverse events, among which interstitial lung disease (ILD) is potentially fatal. The underlying mechanism of ILD induction by ICIs is largely unknown. With the use of flow cytometry, we determined the expression levels of the immune-checkpoint proteins PD-1, TIM-3, TIGIT, LAG-3 and PD-L1 in T cells of bronchoalveolar lavage fluid (BALF) from patients with ICI-related ILD and compared them with those for patients with sarcoidosis or with ILD related to connective tissue disease or cytotoxic drug use. The proportions of CD8+ T cells positive for both PD-1 and TIM-3 or for TIGIT in BALF were significantly higher for ICI-related ILD patients than for those with other types of ILD. A prominent increase in the proportion of PD-1+PD-L1+ cells among CD8+ T cells was also apparent in BALF of a patient with a fatal case of ICI-related ILD, and the proportion of such cells was positively correlated with the grade of ICI-related ILD. Our data reveal the immune-checkpoint profiles of T cells in ICI-related ILD and may provide mechanistic insight into the development of this adverse event.


Subject(s)
Bronchoalveolar Lavage Fluid/immunology , Immune Checkpoint Inhibitors/immunology , Lung Diseases, Interstitial/immunology , T-Lymphocytes/immunology , Adult , Aged , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Lung Diseases, Interstitial/drug therapy , Male , Middle Aged
9.
BMC Infect Dis ; 21(1): 850, 2021 Aug 21.
Article in English | MEDLINE | ID: mdl-34419004

ABSTRACT

BACKGROUND: Although the risk factors for coronavirus disease 2019 (COVID-19) mortality have been identified, there is limited information about the risk factors for disease progression after hospitalization among Japanese patients with COVID-19 exhibiting no or mild symptoms. METHODS: All 302 consecutive patients who were admitted to our institutions and diagnosed with COVID-19 between March and December 2020 were retrospectively assessed. Ultimately, 210 adult patients exhibiting no or mild symptoms on admission were included in the analysis. They were categorized into the stable (no oxygen needed) and worsened (oxygen needed) groups, and their characteristics and laboratory data were compared. RESULTS: Among 210 patients, 49 progressed to a severe disease stage, whereas 161 did not. The mean patient age was 52.14Ā years, and 126 (60.0%) patients were male. The mean body mass index (BMI) was 23.0Ā kg/m2, and 71 patients were overweight (BMI ≥ 25Ā kg/m2). Multivariate logistic analysis showed that old age, overweight, diabetes mellitus (DM), and high serum ferritin levels were independent risk factors for disease progression. CONCLUSIONS: Clinicians should closely observe patients with COVID-19, especially those with risk factors such as old age, overweight, DM, and high serum ferritin levels, regardless of whether they have no or mild symptoms.


Subject(s)
COVID-19 , Disease Progression , Hospitalization , Humans , Infant, Newborn , Japan/epidemiology , Male , Retrospective Studies , Risk Factors , SARS-CoV-2
10.
J Immunol ; 203(8): 2076-2087, 2019 10 15.
Article in English | MEDLINE | ID: mdl-31534007

ABSTRACT

The imbalanced redox status in lung has been widely implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. To regulate redox status, hydrogen peroxide must be adequately reduced to water by glutathione peroxidases (GPx). Among GPx isoforms, GPx4 is a unique antioxidant enzyme that can directly reduce phospholipid hydroperoxide. Increased lipid peroxidation products have been demonstrated in IPF lungs, suggesting the participation of imbalanced lipid peroxidation in IPF pathogenesis, which can be modulated by GPx4. In this study, we sought to examine the involvement of GPx4-modulated lipid peroxidation in regulating TGF-Ɵ-induced myofibroblast differentiation. Bleomycin-induced lung fibrosis development in mouse models with genetic manipulation of GPx4 were examined. Immunohistochemical evaluations for GPx4 and lipid peroxidation were performed in IPF lung tissues. Immunohistochemical evaluations showed reduced GPx4 expression levels accompanied by increased 4-hydroxy-2-nonenal in fibroblastic focus in IPF lungs. TGF-Ɵ-induced myofibroblast differentiation was enhanced by GPx4 knockdown with concomitantly enhanced lipid peroxidation and SMAD2/SMAD3 signaling. Heterozygous GPx4-deficient mice showed enhancement of bleomycin-induced lung fibrosis, which was attenuated in GPx4-transgenic mice in association with lipid peroxidation and SMAD signaling. Regulating lipid peroxidation by Trolox showed efficient attenuation of bleomycin-induced lung fibrosis development. These findings suggest that increased lipid peroxidation resulting from reduced GPx4 expression levels may be causally associated with lung fibrosis development through enhanced TGF-Ɵ signaling linked to myofibroblast accumulation of fibroblastic focus formation during IPF pathogenesis. It is likely that regulating lipid peroxidation caused by reduced GPx4 can be a promising target for an antifibrotic modality of treatment for IPF.


Subject(s)
Idiopathic Pulmonary Fibrosis/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Animals , Bleomycin , Cell Differentiation , Cells, Cultured , Disease Models, Animal , Humans , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/pathology , Lipid Peroxidation , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myofibroblasts/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/deficiency , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Transforming Growth Factor beta/metabolism
11.
Int J Clin Oncol ; 26(12): 2216-2223, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34463869

ABSTRACT

BACKGROUND: Adjuvant oral uracil-tegafur (UFT) has led to significantly longer postoperative survival among patients with non-small-cell lung cancer (NSCLC). Gemcitabine (GEM) monotherapy is also reportedly effective for NSCLC and has minor adverse events (AEs). This study compared the efficacy of GEM- versus UFT-based adjuvant regimens in patients with completely resected pathological stage (p-stage) IB-IIIA NSCLC. PATIENTS AND METHODS: Patients with completely resected p-stage IB-IIIA NSCLC were randomly assigned to GEM or UFT. The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and AEs. RESULTS: We assigned 305 patients to the GEM group and 303 to the UFT group. Baseline factors were balanced between the arms. Of the 608 patients, 293 (48.1%) had p-stage IB disease, 195 (32.0%) had p-stage II disease and 121 (19.9%) had p-stage IIIA disease. AEs were generally mild in both groups, and only one death occurred, in the GEM group. After a median follow-up of 6.8Ā years, the two groups did not significantly differ in survival: 5Ā year OS rates were GEM: 70.0%, UFT: 68.8% (hazard ratio 0.948; 95% confidence interval 0.73-1.23; P = 0.69). CONCLUSION: Although GEM-based adjuvant therapy for patients with completely resected stage IB-IIIA NSCLC was associated with acceptable toxicity, it did not provide longer OS than did UFT.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/surgery , Chemotherapy, Adjuvant , Deoxycytidine/analogs & derivatives , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/surgery , Tegafur , Uracil/therapeutic use , Gemcitabine
12.
Cancer Sci ; 111(3): 924-931, 2020 Mar.
Article in English | MEDLINE | ID: mdl-31943636

ABSTRACT

The formation of premetastatic niches creates a fertile environment for the seeding of disseminated cancer cells in selected secondary organs. This is crucial for the development of metastasis in various malignancies, including breast cancer (BC). We previously reported that the loss of FBXW7 in bone marrow-derived stromal cells promoted cancer metastasis by increasing the production of the chemokine CCL2, which attracts myeloid-derived suppressor cells and macrophages to the premetastatic niche. Furthermore, treatment with the CCL2 inhibitor propagermanium (PG), which has been used in Japan as a therapeutic agent against chronic hepatitis B, was shown to block the enhancement of metastasis in FBXW7-deficient mice through inhibiting the formation of premetastatic niches. Here, we describe a phase I dose-escalation study of PG used as an antimetastatic drug for perioperative patients with primary BC. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Twelve patients were enrolled in the study. Dose-limiting toxicity was not observed, and the maximum dose was determined to be 90Ā mg/body/day. The serum concentrations of PG were nearly within the normal range in all observation days. We observed an inverse correlation between FBXW7 mRNA levels in blood and the serum concentrations of CCL2 and interleukin (IL)-6, in agreement with our previous mouse model. Also, IL-6 was downregulated in a PG dose-dependent manner, as observed in mice. Thus, PG was given safely and it is expected to have antimetastatic potential in BC. This trial is registered in the UMIN Clinical Trials Registry as UMIN000022494.


Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Chemokine CCL2/antagonists & inhibitors , Organometallic Compounds/therapeutic use , Adult , Aged , Breast Neoplasms/genetics , F-Box-WD Repeat-Containing Protein 7/genetics , Female , Germanium , Humans , Interleukin-6/genetics , Japan , Macrophages/drug effects , Middle Aged , Myeloid-Derived Suppressor Cells/drug effects , Propionates , RNA, Messenger/genetics , Signal Transduction/genetics , Young Adult
13.
Cancer Sci ; 111(7): 2482-2487, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32426915

ABSTRACT

The pathogenesis of lung cancer associated with idiopathic pulmonary fibrosis (IPF) has remained largely uncharacterized. To provide insight into this condition, we undertook genomic profiling of IPF-associated lung cancer as well as of adjacent fibrosing lung tissue in surgical specimens. Isolated DNA and RNA from 17 IPF-associated non-small cell lung cancer and 15 paired fibrosing lung tissue specimens were analyzed by next-generation sequencing with a panel that targets 161 cancer-related genes. Somatic genetic alterations were frequently identified in TP53 (nĀ =Ā 6, 35.3%) and PIK3CA (nĀ =Ā 5, 29.4%) genes in tumor samples as well as in EGFR (nĀ =Ā 7, 46.7%), PIK3CA (nĀ =Ā 5, 33.3%), ERBB3 (nĀ =Ā 4, 26.7%), and KDR (nĀ =Ā 4, 26.7%) in IPF samples. Genes related to the RAS-RAF signaling pathway were also frequently altered in tumor (nĀ =Ā 7, 41.2%) and IPF (nĀ =Ā 3, 20.0%) samples. The number of somatic alterations identified in IPF samples was almost as large as that detected in paired tumor samples (81 vs 90, respectively). However, only 6 of the 81 somatic alterations detected in IPF samples overlapped with those in paired tumor samples. The accumulation of somatic mutations was thus apparent in IPF tissue of patients with IPF-associated lung cancer, and the RAS-RAF pathway was implicated in lung tumorigenesis. The finding that somatic alterations were not frequently shared between tumor and corresponding IPF tissue indicates that IPF-associated lung cancer does not develop through the stepwise accumulation of somatic alterations in IPF.


Subject(s)
Genetic Association Studies , Genetic Predisposition to Disease , Idiopathic Pulmonary Fibrosis/genetics , Lung Neoplasms/genetics , Adult , Aged , Biomarkers , Female , Genetic Association Studies/methods , Genetic Testing , Genetic Variation , High-Throughput Nucleotide Sequencing , Humans , Idiopathic Pulmonary Fibrosis/diagnosis , Lung Neoplasms/diagnosis , Male , Middle Aged , Neoplasm Staging , Sequence Analysis, DNA
14.
Cancer ; 126(1): 219-227, 2020 01 01.
Article in English | MEDLINE | ID: mdl-31503343

ABSTRACT

BACKGROUND: The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment. METHODS: Plasma samples were prospectively collected from non-small cell lung cancer patients with EGFR-activating mutations during EGFR-TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next-generation sequencing. RESULTS: One hundred patients, including 87 who were EGFR-TKI naĆÆve, were enrolled. Median progression-free survival was significantly shorter for EGFR-TKI-naĆÆve patients with EGFR-activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0Ā months; PĀ <Ā .001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24Ā weeks than for those who remained positive. An increase in the number of alleles positive for EGFR-activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95% CI, 2.07-10.79; PĀ <Ā .001) for EGFR-TKI-naĆÆve patients showing an increase within 36Ā weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; PĀ =Ā 0.04). CONCLUSION: Liquid biopsy shows potential for prediction of EGFR-TKI efficacy and elucidation of clonal tumor evolution during targeted therapy.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Cell-Free Nucleic Acids/blood , Neoplastic Cells, Circulating/metabolism , Adult , Aged , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , Female , High-Throughput Nucleotide Sequencing/methods , Humans , Liquid Biopsy , Male , Middle Aged , Molecular Targeted Therapy , Mutation/genetics , Neoplastic Cells, Circulating/pathology , Protein Kinase Inhibitors/pharmacology
15.
Cancer ; 126(16): 3648-3656, 2020 08 15.
Article in English | MEDLINE | ID: mdl-32484914

ABSTRACT

BACKGROUND: A randomized phase 3 study was performed to investigate the efficacy and safety of maintenance therapy with S-1 after induction therapy with carboplatin plus S-1 in patients with advanced squamous non-small cell lung cancer (NSCLC). METHODS: Chemotherapy-naive patients with advanced or relapsed squamous NSCLC were treated with carboplatin (area under the curve of 5 on day 1 every 3Ā weeks) plus S-1 (40Ā mg/m2 twice per day on days 1-14 every 3Ā weeks) as induction therapy. Patients who did not progress after 4 cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective of the study was to confirm the superiority of S-1 plus BSC in comparison with BSC alone with respect to progression-free survival. RESULTS: Of the 365 patients enrolled in the study, 347 participated in the induction phase, and 131 of these individuals were randomized to receive S-1 plus BSC (nĀ =Ā 67) or BSC alone (nĀ =Ā 64). The risk of disease progression was significantly lower for patients in the S-1 plus BSC arm than those in the BSC-alone arm (hazard ratio, 0.548; 95% confidence interval, 0.374-0.802; PĀ =Ā .0019). The most common toxicities during maintenance therapy with S-1 included anorexia, anemia, and fatigue, but most cases were not severe. CONCLUSIONS: Continued maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC previously treated with carboplatin plus S-1.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Lung Neoplasms/drug therapy , Lung/drug effects , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carcinoma, Squamous Cell/epidemiology , Carcinoma, Squamous Cell/pathology , Cisplatin/administration & dosage , Cisplatin/adverse effects , Drug Combinations , Humans , Induction Chemotherapy , Lung/pathology , Lung Neoplasms/epidemiology , Lung Neoplasms/pathology , Male , Middle Aged , Oxonic Acid/administration & dosage , Oxonic Acid/adverse effects , Pemetrexed/administration & dosage , Pemetrexed/adverse effects , Progression-Free Survival , Proportional Hazards Models , Tegafur/administration & dosage , Tegafur/adverse effects , Treatment Outcome
16.
Oncologist ; 25(3): 208-e417, 2020 03.
Article in English | MEDLINE | ID: mdl-32162814

ABSTRACT

LESSONS LEARNED: The biweekly GEM plus CBDCA dose and schedule showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC. The biweekly GEM plus CBDCA regimen could be considered an alternative to the 3-week regimen in NSCLC. BACKGROUND: The gemcitabine (GEM)-carboplatin (CBDCA) combination is widely used for non-small cell lung cancer (NSCLC) and has some efficacy in elderly patients; however, a high incidence of thrombocytopenia is observed, and the optimal dosage and administration schedules are unknown. This multicenter phase II trial evaluated the efficacy and tolerability of GEM-CBDCA for elderly patients with chemotherapy-naive NSCLC. METHODS: Patients with chemotherapy-naive performance status 0-1 and with stage IIIB/IV NSCLC were administered chemotherapy biweekly (GEM 1,000 mg/m2 with CBDCA area under the blood concentration-time curve (AUC) 3 on days 1 and 15 every 4 weeks). The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty-eight patients were enrolled. Median age was 76 years (range, 70-83); 35 patients were men (73%), and 27 patients had adenocarcinoma (56%). The ORR was 29.2% (95% confidence interval [CI], 17.0-44.1). The median PFS, median OS, and 1-year survival was 5.9 months (95% CI, 4.1-6.6), 13.3 months (95% CI, 8.3-23.5), and 58%, respectively. Grade ≥3 hematological toxicities included neutropenia (29.2%), thrombocytopenia (4.2%), and anemia (20.8%). The incidence of grade ≥3 nonhematological toxicities was <5%. CONCLUSION: This GEM-CBDCA combination administered biweekly showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/analogs & derivatives , Female , Humans , Lung Neoplasms/drug therapy , Male , Treatment Outcome , Gemcitabine
17.
Oncologist ; 25(6): 475-e891, 2020 06.
Article in English | MEDLINE | ID: mdl-31649134

ABSTRACT

LESSONS LEARNED: Updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy were collected. In the group of 58 patients who were enrolled at 14 institutions in Japan, the median overall survival was not reached and the 2-year overall survival rate was 66.1% (95% confidence interval, 52.1%-76.8%). Results reveal encouraging feasibility and activity for this regimen. BACKGROUND: We report the updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel (nab-P/C) and concurrent radiotherapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC). METHODS: Individuals between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. Patients received weekly nab-paclitaxel at 50 mg/m2 for 6 weeks together with weekly carboplatin at an area under the curve (AUC) of 2 mg/ml/min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel (100 mg/m2 on days 1, 8, and 15) plus carboplatin (AUC of 6 on day 1). After the treatment, patients were observed off therapy. The primary endpoint of the phase II part of the study was progression-free survival (PFS). RESULTS: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0-49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1%-76.8%). The median PFS was 11.8 months (95% CI, 8.2-21.0 months), and the 2-year PFS rate was 35.9% (95% CI, 23.1%-48.9%). Subgroup analysis according to tumor histology or patient age revealed no differences in median PFS or OS. Long-term follow-up of toxicities did not identify new safety signals, and no treatment-related deaths occurred during the study period. CONCLUSION: Concurrent chemoradiation with nab-P/C was safe and provided a long-term survival benefit for patients with locally advanced NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Albumins , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Humans , Japan , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Paclitaxel/therapeutic use
18.
Oncologist ; 25(4): 306-e618, 2020 04.
Article in English | MEDLINE | ID: mdl-32297438

ABSTRACT

LESSONS LEARNED: Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status. Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases. BACKGROUND: We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients. METHODS: Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study. RESULTS: The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1-30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8-64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886). CONCLUSION: Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Anaplastic Lymphoma Kinase/genetics , Carbazoles/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Crizotinib , Humans , Lung , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Piperidines , Protein Kinase Inhibitors/therapeutic use , Survival Analysis
19.
Oncologist ; 24(11): 1420-e1010, 2019 11.
Article in English | MEDLINE | ID: mdl-31332099

ABSTRACT

LESSONS LEARNED: This clinical trial, evaluating the efficacy and safety of a carboplatin plus paclitaxel regimen in a biweekly or weekly schedule instead of the more toxic 3-weekly administration, showed that the weekly regimen was better in efficacy than the biweekly regimen, with mild toxicities, for patients with non-small cell lung cancer (NSCLC).The weekly carboplatin plus paclitaxel regimen could be considered as an alternative to the 3-weekly regimen in Japanese patients with NSCLC. BACKGROUND: Combination therapy comprising carboplatin (C) and paclitaxel (P) is the most commonly used regimen for the treatment of advanced non-small cell lung cancer (NSCLC). Common toxicities associated with the regimen, such as neuropathy and myelosuppression, cause its discontinuation. In the present study, we conducted a clinical trial evaluating the efficacy of biweekly (B) and weekly (W) PC therapy to identify the appropriate chemotherapy schedule for Asian patients. METHODS: Chemonaive patients with IIIB/IV NSCLC and a performance status of 0-1 were randomly assigned to a biweekly regimen (paclitaxel 135 mg/m2 with carboplatin area under the curve [AUC] 3 on days 1 and 15 of every 4 weeks) or to a weekly regimen (paclitaxel 90 mg/m2 on days 1, 8, and 15 with carboplatin AUC 6 on day 1 of every 4 weeks). RESULTS: A total of 140 patients were enrolled in the study. The objective response rates (ORRs) were 28.1% (B) and 38.0% (W). The most common toxicity was neutropenia, with incidence rates of 62.0% (B) and 57.8% (W). Progression-free survivals (PFSs) were 4.3 months (B) and 5.1 months (W), and overall survival durations were 14.2 months (B) and 13.3 months (W). CONCLUSION: The ORR and PFS in the weekly regimen were better than those in the biweekly schedule, although a statistical difference was not observed. The toxicity profile was generally mild for both regimens. The weekly CP regimen was suitable to be considered as an alternative to the current 3-weekly regimen in NSCLC treatment.


Subject(s)
Adenocarcinoma of Lung/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Lung Neoplasms/drug therapy , Adenocarcinoma of Lung/pathology , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/pathology , Female , Follow-Up Studies , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Paclitaxel/administration & dosage , Prognosis , Survival Rate
20.
Oncologist ; 24(8): 1022-1026, 2019 08.
Article in English | MEDLINE | ID: mdl-31023862

ABSTRACT

Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP-Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first- or second-generation EGFR-TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP-Seq successfully. Original activating EGFR mutations were detected in 23 patients, with the remaining patient showing MET amplification. With regard to known mechanisms of EGFR-TKI resistance, the T790M mutation of EGFR was detected in 17 of the 24 patients, MET amplification in 9 patients (6 of whom also harbored T790M), ERBB2 amplification in 2 patients (1 of whom also harbored T790M), and EGFR amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first- or second-generation EGFR-TKIs. Patients positive for the T790M mutation of EGFR were also found to constitute a molecularly heterogeneous population. KEY POINTS: CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations.The T790M mutation of EGFR is associated with amplification of MET, ERBB2, or EGFR in NSCLC patients resistant to EGFR-TKIs.T790M-positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first-generation or second-generation EGFR-TKIs.


Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , DNA Mutational Analysis/methods , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/genetics , Circulating Tumor DNA/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Feasibility Studies , Female , Gene Amplification , High-Throughput Nucleotide Sequencing , Humans , Lung Neoplasms/blood , Lung Neoplasms/genetics , Male , Middle Aged , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/genetics , Receptor, ErbB-2/genetics
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