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INTRODUCTION: Psychological disorders, such as depression, are markedly prevalent in patients with airway diseases. In this study, we assessed the effect of treatment with dupilumab, an IL-4 receptor α chain antibody, on depressive symptoms in a cohort of patients with asthma with eosinophilic chronic rhinosinusitis (ECRS). METHODS: The study participants, diagnosed with asthma and ECRS, were assessed for symptoms and quality of life (QOL) scores for asthma and ECRS and medications. The Patient Health Questionnaire-9 (PHQ-9) scores were used to evaluate the depressive state. The depressive symptoms were compared with asthma and ECRS symptoms both at the time of initiation and after 4 months of dupilumab treatment. RESULTS: Ultimately, 31 patients were included in the study. Most patients demonstrated a depressive state that was correlated with the nasal symptom score. In the evaluation 4 months after dupilumab treatment, the PHQ-9 score was significantly reduced, and the decrease was remarkable in patients whose nasal symptom score was reduced by 50% or more. Additionally, the PHQ-9 scores in patients with improved nasal and asthma symptoms were significantly reduced. DISCUSSION/CONCLUSION: Dupilumab may improve QOL in patients with bronchial asthma with ECRS by reducing depressive symptoms through the improvement of clinical symptoms.
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Asma , Pólipos Nasales , Rinitis , Sinusitis , Anticuerpos Monoclonales Humanizados , Asma/complicaciones , Asma/tratamiento farmacológico , Asma/epidemiología , Enfermedad Crónica , Depresión , Humanos , Japón , Pólipos Nasales/tratamiento farmacológico , Calidad de Vida , Rinitis/complicaciones , Rinitis/diagnóstico , Rinitis/tratamiento farmacológico , Sinusitis/complicaciones , Sinusitis/diagnóstico , Sinusitis/tratamiento farmacológicoRESUMEN
Lymphodepleting cytotoxic regimens enhance the antitumor effects of adoptively transferred effector and naïve T cells. Although the mechanisms of antitumor immunity augmentation by lymphodepletion have been intensively investigated, the effects of lymphodepletion followed by T cell transfer on immune checkpoints in the tumor microenvironment remain unclear. The current study demonstrated that the expression of immune checkpoint molecules on transferred donor CD4+ and CD8+ T cells was significantly decreased in lymphodepleted tumor-bearing mice. In contrast, lymphodepletion did not reduce immune checkpoint molecule levels on recipient CD4+ and CD8+ T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Further analysis revealed that transfer of both donor CD4+ and CD8+ T cells was responsible for the antitumor effects of a combination therapy consisting of lymphodepletion, T cell transfer and anti-PD-1 treatment. Our findings indicate that a possible mechanism underlying the antitumor effects of lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. PD-1 blockade may reinvigorate exhausted recipient T cells and augment the antitumor effects of lymphodepletion and adoptive T cell transfer.
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Linfocitos T CD8-positivos , Neoplasias , Traslado Adoptivo , Animales , Humanos , Inmunoterapia Adoptiva , Ratones , Neoplasias/terapia , Receptor de Muerte Celular Programada 1 , Microambiente TumoralRESUMEN
OBJECTIVES: Although immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs. METHODS: We retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors. RESULTS: Of 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) vs. not reached (95% CI: 22.4-NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) vs. not reached (95% CI: 8.4-NE); p = 0.031]. CONCLUSION: The current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.
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BACKGROUND: Although immune checkpoint inhibitors (ICIs) are effective for advanced non-small cell lung cancer (NSCLC), ICIs may cause interstitial lung disease (ILD), which results in treatment discontinuation and is sometimes fatal. Despite the high incidence of ICI-related ILD, there are few cancer treatment options for patients. This study aimed to evaluate the safety and efficacy of subsequent systemic cancer therapy in NSCLC patients with ICI-related ILD. METHODS: We retrospectively assessed NSCLC patients who received programmed cell death-1 (PD-1) inhibitors as first- to third-line therapy at participating institutions of the Niigata Lung Cancer Treatment Group from January 2016 to October 2017. RESULTS: This analysis included 231 patients, 32 (14%) of whom developed ICI-related ILD. Of these patients, 16 (7%) received subsequent systemic cancer treatments. The median overall survival (OS) tended to be longer in the systemic cancer therapy group than in the no systemic cancer therapy group [22.2 months (95% CI: 1-NE) vs. 4.5 months (95% CI: 1-NE); P=0.067]. ICI-related ILD recurred in half of the patients who received systemic cancer therapy, and the median OS tended to be shorter in patients with recurrent ICI-related ILD [22.0 months (95% CI: 1-NE) vs. 7.0 months (95% CI: 1-NE); P=0.3154]. CONCLUSIONS: According to the current study, systemic cancer treatment is effective in patients with ICI-related ILD; however, its safety is uncertain because of the high risk of ICI-related ILD recurrence and poor survival outcome following ILD recurrence.
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We herein report the case of a 20 year-old-man who developed bronchiolitis obliterans after living-donor renal transplantation. The patient presented with dyspnea on exertion and wheezing two years after renal transplantation, and spirometry showed an obstructive pattern. Surgical lung biopsy revealed subepithelial fibrosis that constricted and obstructed the intrabronchiolar space. Based on these findings, the patient was diagnosed with bronchiolitis obliterans. He was prescribed bronchodilators and azithromycin, and he achieved stable respiratory function for two years. The differential diagnosis of respiratory symptoms after renal transplantation includes opportunistic infection and drug-induced lung injury; however, bronchiolitis obliterans should also be considered.
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Bronquiolitis Obliterante/diagnóstico , Bronquiolitis Obliterante/etiología , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Donadores Vivos , Complicaciones Posoperatorias/etiología , Adulto , Azitromicina/uso terapéutico , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/patología , Broncodilatadores/uso terapéutico , Diagnóstico Diferencial , Fibrosis , Humanos , Pulmón/patología , Pulmón/fisiopatología , Masculino , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/patología , Espirometría , Adulto JovenRESUMEN
A 31-year-old woman who was clinically diagnosed with Silver-Russell syndrome (SRS) in childhood was admitted with complaints of dyspnea. She had hypercapnic respiratory failure accompanied by nocturnal hypoventilation. Computed tomography revealed systemic muscle atrophy and superior mesenteric artery syndrome; however, the bilateral lung fields were normal. She was treated with nocturnal noninvasive positive pressure ventilation and showed improvement of respiratory failure. In this case, loss of methylation on chromosome 11p15 and maternal uniparental disomy of chromosome 7, which are the common causes of SRS, were not detected. This is a rare case of adult SRS manifesting as chronic hypercapnic respiratory failure.
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Insuficiencia Respiratoria , Síndrome de Silver-Russell , Adulto , Femenino , Humanos , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/genética , Síndrome de Silver-Russell/complicaciones , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Disomía UniparentalRESUMEN
Cisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias del Colon/tratamiento farmacológico , Insuficiencia Renal/prevención & control , Animales , Apoptosis , Proliferación Celular , Cilastatina/administración & dosificación , Cisplatino/administración & dosificación , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Tasa de Filtración Glomerular , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Endogámicos NOD , Ratones SCID , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Viral pneumonia caused by varicella-zoster virus (VZV) infection is a rare but important complication, especially regarding varicella infections. Although disseminated cutaneous herpes zoster (DCHZ) is often associated with visceral diseases, there have been few reports of DCHZ-related pneumonia. We herein report a rare case of a lethal disseminated VZV infection that caused severe pneumonia in a Japanese patient who had chronic interstitial pneumonia. Physicians should consider the possibility of VZV-related pneumonia, especially in patients with a medical history of hematopoietic stem cell transplantation and immunosuppressive therapy.
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Varicela , Herpes Zóster , Enfermedades Pulmonares Intersticiales , Neumonía , Antivirales/uso terapéutico , Varicela/tratamiento farmacológico , Herpes Zóster/complicaciones , Herpes Zóster/diagnóstico , Herpes Zóster/tratamiento farmacológico , Herpesvirus Humano 3 , Humanos , Huésped Inmunocomprometido , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico , Neumonía/tratamiento farmacológicoAsunto(s)
Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Asma/metabolismo , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Esputo/metabolismo , Antiasmáticos/farmacología , Anticuerpos Monoclonales Humanizados/farmacología , Asma/diagnóstico , Biomarcadores , Humanos , Resultado del TratamientoRESUMEN
It is well known that the prevalence of asthma is higher in athletes, including Olympic athletes, than in the general population. In this study, we analyzed the mechanism of exercise-induced bronchoconstriction by using animal models of athlete asthma. Mice were made to exercise on a treadmill for a total duration of 1 week, 3 weeks, or 5 weeks. We analyzed airway responsiveness, BAL fluid, lung homogenates, and tissue histology for each period. In mice that were treated (i.e., the treatment model), treatments were administered from the fourth to the fifth week. We also collected induced sputum from human athletes with asthma and analyzed the supernatants. Airway responsiveness to methacholine was enhanced with repeated exercise stimulation, although the cell composition in BAL fluid did not change. Exercise induced hypertrophy of airway smooth muscle and subepithelial collagen deposition. Cysteinyl-leukotriene (Cys-LT) levels were significantly increased with exercise duration. Montelukast treatment significantly reduced airway hyperresponsiveness (AHR) and airway remodeling. Expression of PLA2G4 (phospholipase A2 group IV) and leukotriene C4 synthase in the airway epithelium was upregulated in the exercise model, and inhibition of PLA2 ameliorated AHR and airway remodeling, with associated lower levels of Cys-LTs. The levels of Cys-LTs in sputum from athletes did not differ between those with and without sputum eosinophilia. These data suggest that AHR and airway remodeling were caused by repeated and strenuous exercise. Cys-LTs from the airway epithelium, but not inflammatory cells, may play an important role in this mouse model.
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Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Broncoconstricción/fisiología , Cisteína/metabolismo , Fosfolipasas A2 Grupo II/metabolismo , Leucotrienos/metabolismo , Condicionamiento Físico Animal/fisiología , Acetatos/farmacología , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Animales , Asma/tratamiento farmacológico , Asma/metabolismo , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/metabolismo , Broncoconstricción/efectos de los fármacos , Ciclopropanos , Femenino , Leucotrienos/farmacología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Cloruro de Metacolina/farmacología , Ratones , Ratones Endogámicos BALB C , Quinolinas/farmacología , Hipersensibilidad Respiratoria/tratamiento farmacológico , Hipersensibilidad Respiratoria/metabolismo , SulfurosRESUMEN
BACKGROUND: Interstitial lung disease (ILD) induced by anti-programmed-cell death-1 (PD-1) and anti-PD-ligand 1 (PD-L1) is potentially life-threatening and is a common reason of the discontinuation of therapy. In contrast, an enhancement in antitumor effects was reported in patients who developed immune-related adverse events, including ILD. Although recent evidence suggests that radiologic patterns of ILD may reflect the severity of ILD and the antitumor immune responses to anti-PD-1/PD-L1 therapies, the association between radiologic features and clinical outcomes remains unclear. METHODS: Patients with advanced non-small-cell lung cancer who were treated with 1st to 3rd line anti-PD-1 therapy from January 2016 through October 2017 were identified at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. ILD was diagnosed by the treating physicians, and chest computed tomography scans were independently reviewed to assess the radiologic features of ILD. RESULTS: A total of 231 patients who received anti-PD-1 therapy were enrolled. Thirty-one patients (14%) developed ILD. Sixteen patients were classified as having ground glass opacities (GGO), 16 were classified as having cryptogenic organizing pneumonia (COP), and one was classified as having pneumonitis not otherwise specified. Patients with GGO had significantly worse overall survival time compared to patients with COP (7.8 months (95% CI: 2.2-NE) versus not reached (95% CI: 13.2-NE); P = 0.0175). Multivariate analysis of all 231 patients also revealed that PS = 1 and ≥2 and GGO were significant predictors of a worse overall survival. CONCLUSIONS: This study demonstrated that patients who developed GGO exhibited worse outcomes among non-small-cell lung cancer patients receiving anti-PD-1 therapies.
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Antineoplásicos Inmunológicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neumonía/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Tomografía Computarizada por Rayos X/métodos , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Neumonía/inducido químicamente , Neumonía/diagnóstico por imagen , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
INTRODUCTION/OBJECTIVES: Interstitial lung disease (ILD) is a significant cause of mortality among patients with dermatomyositis (DM) or polymyositis (PM). There are two subtypes of PM and DM often complicated with ILD: those with anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies and those with anti-MDA-5-associated amyopathic DM (ADM). Our aim is to clarify the inflammatory and immunological differences between the disorders. METHODS: We retrospectively collected consecutive patients with anti-ARS-ILD and those with anti-MDA-5 antibody-positive ADM-ILD. The serum concentration of 38 cytokines was measured using a cytokine panel. The relative risks for anti-MDA-5 antibody-positive ADM-ILD were examined with univariate and multivariate logistic regression models. Spearman's rank correlation coefficient was calculated between cytokine levels and clinical parameters in the disease. Levels of cytokines were compared between anti-ARS-ILD and anti-MDA-5-positive ADM-ILD patients (alive or dead) using Dunnett's test. RESULTS: Twenty-three patients with anti-ARS-ILD and the same number of patients with anti-MDA-5-positive ADM-ILD were enrolled. The anti-MDA-5 group had poor survival (p = 0.025). Univariate logistic regression models showed that eotaxin, IL-10, IP-10, and MCP-1 were associated with the diagnosis of anti-MDA-5-positive ADM-ILD. Multivariate logistic regression models revealed that IP-10 was the most significantly associated (p = 0.001). Relationship analyses showed that IL-10 had significant positive correlations with CK (r = 0.5267, p = 0.009) and ferritin (r = 0.4528, p = 0.045). A comparison of the cytokine levels found that IP-10 was elevated in both patients who were alive and patients who had died with ADM-ILD compared with the levels in those with ARS-ILD (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Anti-MDA-5-positive ADM-ILD had poorer survival than anti-ARS-ILD. IP-10 seems to be most deeply involved in the pathophysiology of anti-MDA-5-associated ADM-ILD.Key Points⢠To clarify differences in the inflammatory and immunological features of anti-MDA-5-positive ADM-ILD and anti-ARS-ILD, we performed an observational study to measure serum cytokine concentrations before treatment using a multiplex immunoassay system.⢠Multivariate logistic regression models revealed that IP-10 was associated with the most significant relative risk for ADM-ILD with anti-MDA-5 antibodies.⢠Levels of IP-10 were elevated considerably in anti-MDA-5-positive survivors and nonsurvivors compared with the levels in anti-ARS patients.⢠These results suggest that IP-10 is the most deeply involved in the pathophysiology of anti-MDA-5-positive ADM-ILD.
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Autoanticuerpos/sangre , Quimiocina CXCL10/sangre , Dermatomiositis/inmunología , Enfermedades Pulmonares Intersticiales/inmunología , Polimiositis/inmunología , Anciano , Aminoacil-ARNt Sintetasas/inmunología , Citocinas/sangre , Dermatomiositis/complicaciones , Femenino , Humanos , Helicasa Inducida por Interferón IFIH1/inmunología , Modelos Logísticos , Enfermedades Pulmonares Intersticiales/sangre , Masculino , Persona de Mediana Edad , Análisis Multivariante , Polimiositis/complicaciones , Pronóstico , Estudios Retrospectivos , Sobrevivientes/estadística & datos numéricosRESUMEN
Background: The anti-immunoglobulin E monoclonal antibody, omalizumab, is used to treat severe asthma and has the potential to ameliorate airway inflammation. However, the effect of omalizumab in ameliorating upper airway inflammation has not been fully elucidated. Objective: We investigated the association of upper and lower airway inflammation with the response to omalizumab treatment. Methods: We used the Global Evaluation of Treatment Effectiveness to assess the efficacy of omalizumab in treating 16 patients with severe asthma. We also investigated the symptom score, short-acting ß-agonist inhaler use, pulmonary function, biomarkers, computed tomography scans, and nasal mucosa pathology at omalizumab initiation and after four months of treatment. Results: When the fraction of exhaled nitric oxide (FeNO) and the percentage of sputum eosinophil were used as indicators of lower airway inflammation, positive correlations were found between CD20 B-cell, mast cell, and eosinophil counts in the nasal mucosa. Improved asthma symptoms were observed in 12 of the 16 severe asthma cases. The FeNO and eosinophil levels in the nasal tissue, prior to the administration of omalizumab were predictors of the response to asthma treatment. Conclusions: These findings suggest heterogeneity among people with severe asthma. In addition, the phenotype associated with response to omalizumab, leading to improvement in asthma symptoms, comprises upper airway eosinophilia and high FeNO levels.
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Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Eosinófilos/inmunología , Mucosa Nasal/inmunología , Omalizumab/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antiasmáticos/farmacología , Asma/diagnóstico , Asma/inmunología , Linfocitos B/inmunología , Eosinófilos/efectos de los fármacos , Espiración , Femenino , Humanos , Recuento de Leucocitos , Masculino , Mastocitos/inmunología , Persona de Mediana Edad , Mucosa Nasal/citología , Mucosa Nasal/efectos de los fármacos , Óxido Nítrico/análisis , Omalizumab/farmacología , Pronóstico , Índice de Severidad de la Enfermedad , Esputo/citología , Esputo/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: As indices of asthma control, exacerbations are equally important with symptoms and respiratory function. Thus, it is critical to recognize the risk factors of exacerbation. OBJECTIVE: We conducted a questionnaire survey of asthma patients in Niigata Prefecture to clarify the factors involved in asthma exacerbation. METHODS: The questionnaire survey was carried out in patients and their physicians from September to October 2014. In 2015, the same sample population also received a questionnaire about current asthma control and exacerbation. RESULTS: One hundred patients experienced asthma exacerbation during the 1-year period. There were significant differences in age, sex, history of hospitalization due to asthma, smoking history, Asthma Control Test, treatment step, and transient steroid treatment history in the previous year between the exacerbation group and non-exacerbation group. On multivariate analysis, there was a significant difference in history of transient steroid therapy, history of hospitalization associated with asthma attacks, and nonsmoking history. Cluster analysis of cases with exacerbation was classified into three clusters. Cluster 1 comprised slightly older cases with smoking history, Cluster 2 had more females, non-smoking and nonatopic cases with uncontrolled symptoms, and Cluster 3 had more females, non-smoking and mild atopic cases. CONCLUSIONS: Our findings suggest that patients with asthma exacerbation in the previous year and nonsmoking females are important targets for the study of asthma exacerbation. The adequate treatment of women patients might be important for the prevention of asthma exacerbation.
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Asma/epidemiología , Hospitalización/estadística & datos numéricos , Factores Sexuales , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
BACKGROUND: Adherence Starts with Knowledge-12 (ASK-12) is a useful indicator of drug adherence. In this study, we analyzed patient background including social and psychological factors in a low-adherence group of patients with asthma defined using ASK-12. METHODS: From a questionnaire survey for patients with asthma from the Niigata Prefecture, Japan, conducted in the fall of 2016, we enrolled patients who answered all ASK-12 items and underwent a measured respiratory function test within 1 year. The low-adherence group (ASK-12 ≥ 28) was compared with the control group (ASK-12 < 28), and we conducted a cluster analysis of the low-adherence group. RESULTS: There were 170 patients in the low-adherence group and 402 patients in the control group. There was a significant difference between age, gender, working status, smoking history, the percentage of forced expiratory volume in one second (%FEV1), asthma control test (ACT), and Patient Health Questionnaire-9 (PHQ-9) score between the two groups. Logistic analysis revealed that working status (working), % FEV1 (<90%), and PHQ-9 score (>5) were independent factors for the low-adherence group. The cluster analysis identified three clusters in the low-adherence group. Among these, one cluster was characterized by elderly males with chronic obstructive pulmonary disease and another by middle-aged nonsmoking females with a depression tendency, had problems with asthma control. CONCLUSIONS: Several factors were considered to be attributed to low drug-adherence. There were several phenotypes in the low-adherence population correlated with incomplete asthma control. Intervention with drug adherence should be a future goal for asthma treatment.
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Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Cumplimiento de la Medicación/estadística & datos numéricos , Anciano , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
Although the blockade of programmed cell death 1 (PD-1)/PD-ligand (L) 1 has demonstrated promising and durable clinical responses for non-small-cell lung cancers (NSCLCs), NSCLC patients with epidermal growth factor receptor (EGFR) mutations responded poorly to PD-1/PD-L1 inhibitors. Previous studies have identified several predictive biomarkers, including the expression of PD-L1 on tumor cells, for PD-1/PD-L1 blockade therapies in NSCLC patients; however, the usefulness of these biomarkers in NSCLCs with EGFR mutations has not been elucidated. The present study was conducted to evaluate the predictive biomarkers for PD-1/PD-L1 inhibitors in EGFR-mutated NSCLCs. We retrospectively analyzed 9 patients treated with nivolumab for EGFR-mutated NSCLCs. All but one patient received EGFR-tyrosine kinase inhibitors before nivolumab treatment. The overall response rate and median progression-free survival were 11% and 33 days (95% confidence interval (CI); 7 to 51), respectively. Univariate analysis revealed that patients with a good performance status (P = 0.11; hazard ratio (HR) 0.183, 95% CI 0.0217 to 1.549), a high density of CD4+ T cells (P = 0.136; HR 0.313, 95% CI 0.045 to 1.417) and a high density of Foxp3+ cells (P = 0.09; HR 0.264, 95% CI 0.0372 to 1.222) in the tumor microenvironment tended to have longer progression-free survival with nivolumab. Multivariate analysis revealed that a high density of CD4+ T cells (P = 0.005; HR<0.001, 95% CI <0.001 to 0.28) and a high density of Foxp3+ cells (P = 0.003; HR<0.001, 95% CI NA) in tumor tissues were strongly correlated with better progression-free survival. In contrast to previous studies in wild type EGFR NSCLCs, PD-L1 expression was not associated with the clinical benefit of anti-PD-1 treatment in EGFR-mutated NSCLCs. The current study indicated that immune status in the tumor microenvironment may be important for the effectiveness of nivolumab in NSCLC patients with EGFR mutations.
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Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Nivolumab/uso terapéutico , Adulto , Anciano , Antígeno B7-H1/antagonistas & inhibidores , Biomarcadores de Tumor/inmunología , Recuento de Linfocito CD4 , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Receptores ErbB/genética , Femenino , Factores de Transcripción Forkhead/metabolismo , Genes erbB-1 , Humanos , Neoplasias Pulmonares/inmunología , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estudios Retrospectivos , Microambiente Tumoral/inmunologíaRESUMEN
Objective High adherence to medications and accurate handling of inhaler devices are important for asthma management. However, few reports to date have simultaneously evaluated adherence and handling errors. We therefore investigated the adherence to inhaled corticosteroid (ICS) and inhaler handling errors in the same patients in cooperation with pharmacists. Methods Data were derived from a survey of physicians and pharmacists treating asthma patients who visited participating hospitals and pharmacies from July 2012 to January 2013. The patients were evaluated for asthma control using the Asthma Control Test (ACT) and for inhaler handling errors using checklists. ICS adherence was evaluated based on pharmaceutical records. Results Adherence among participants (n=290) was 33.3% (mean), and the percentage of inhaler handling errors was 20.0% (mean). Total inhalation times in the high-adherence group were fewer than those in the low-adherence group. In a comparison by device, adherence to pressurized metered dose inhalers was significantly lower than that to Diskus® inhalers, presumably attributable to the total number of inhalations per day. Adherence, handling errors, and total number of inhalations per day were significantly different between the asthma-controlled group and the uncontrolled group. A multivariate analysis showed that adherence and handling errors were independent factors contributing to asthma control. Conclusion Our data indicated that both adherence to ICS and device handling errors contributed to asthma control in this population.
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Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Cumplimiento de la Medicación , Nebulizadores y Vaporizadores , Administración por Inhalación , Adulto , Anciano , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
BACKGROUND: Anti-MDA-5 antibody is closely associated with interstitial lung disease (ILD) in amyopathic dermatomyositis (ADM). Patients with ADM with anti-MDA-5 antibody sometimes develop fatal ILD in spite of intensive immunosuppressive therapy. However, an initial decrease after treatment in anti-MDA-5 antibody titers may not be predictive of subsequent better survival of the disease. METHODS: To clarify immunoregulatory features of deadly ILD in ADM with the anti-MDA-5 antibody, we retrospectively examined clinical records of consecutive patients with anti-MDA-5 antibody positive ADM-ILD with preserved serum since 2000. Serum cytokine/growth factor (GF) protein concentration was measured using a cytokine panel analysis. We compared concentrations of each cytokine/GF between survivors and non-survivors and further examined changes in cytokines/GF levels during treatment in some patients. RESULTS: Twenty-six patients were enrolled in the study. Nine out of 26 patients did not respond to intensive immunosuppressive therapy and died due to respiratory failure. We compared cytokine/GF concentrations and found that serum IL-15 before treatment was significantly elevated in non-survivors than in survivors (pâ¯<â¯0.05). 11 out of 17 responders and 6 of 9 dead patients had preserved serum taken more than one time. We then calculated rates of change per day (slopes) in each cytokine/GF concentration. Comparison of slopes of cytokine/GF protein over the treatment duration showed that the slopes in non-survivors were significantly increased in IL-10 and IL-15 (pâ¯<â¯0.01). CONCLUSIONS: IL-15, as well as IL-10, may play a key role in the progression of the patients with ADM-ILD with anti-MDA-5 antibody positive.
Asunto(s)
Autoanticuerpos/sangre , Dermatomiositis/inmunología , Helicasa Inducida por Interferón IFIH1/sangre , Interleucina-10/sangre , Interleucina-15/sangre , Enfermedades Pulmonares Intersticiales/inmunología , Adulto , Anciano , Estudios Transversales , Citocinas/sangre , Dermatomiositis/complicaciones , Dermatomiositis/tratamiento farmacológico , Progresión de la Enfermedad , Femenino , Humanos , Inmunosupresores/uso terapéutico , Helicasa Inducida por Interferón IFIH1/efectos de los fármacos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Insuficiencia Respiratoria/mortalidad , Estudios Retrospectivos , Sobrevivientes/estadística & datos numéricosRESUMEN
A 59-year-old Japanese man diagnosed with interstitial lung disease associated with amyopathic dermatomyositis with anti-melanoma differentiation-associated gene 5 (MDA-5) antibodies was treated with intravenous methyl prednisolone (PSL) 1000 mg, oral PSL 1 mg/kg, and oral cyclosporin 200 mg daily. His respiratory condition worsened after treatment with two times of intravenous cyclophosphamide and another steroid pulse therapy as well as PSL and cyclosporin. Addition of mycophenolate mofetil (MMF), 1.5 g daily improved PaO2/FiO2 (PF) ratio of the patient from 294 to 360 at 4 weeks and 416 at 15 weeks after addition of MMF. We measured cytokine concentration in preserved serum taken at 11 and 7 weeks before addition of MMF and at 4, 11, and 15 weeks after MMF administration. Of the 28 cytokines evaluated, the concentrations of fibroblast growth factors-2 (FGF-2), chemokine (C-X3-C motif) ligand 1 (CX3CL1), interleukin (IL)-1ra, IL-17A, inducible protein 10 (IP-10), and monocyte chemotactic protein-1 (MCP-1) decreased after addition of MMF. These results suggest that MMF may be beneficial to patients with interstitial lung disease by modification of the cytokine/growth factor protein expression.
RESUMEN
BACKGROUND: Asthma in athlete populations such as Olympic athletes has various pathogeneses. However, few reports are available on the features of asthma in the athlete population in clinical practice. In this study, we focused on classifying asthma in Japanese athlete population. METHODS: We performed a cluster analysis of data from pulmonary function tests and clinical biomarkers before administering inhaled corticosteroids (ICS) therapy in athlete population of individuals diagnosed with asthma (n = 104; male, 76.9%; median age, 16.0 years), based on respiratory symptoms and positive data on methacholine provocation tests. We also compared backgrounds, sports types, and treatments between clusters. RESULTS: Three clusters were identified. Cluster 1 (32%) comprised athletes with a less atopic phenotype and normal pulmonary function. Cluster 2 (44%) comprised athletes with a less atopic phenotype and lower percent predicted forced expiratory volume in 1 s (%FEV1) values, despite less symptomatic state. Cluster 3 (24%) comprised athletes with a strong atopic phenotype such as high eosinophil count in the blood and total serum immunoglobulin E level. After treatment with ICS or ICS plus long-acting ß-adrenergic receptor agonist for 6-12 months, %FEV1 values were significantly improved in Cluster 2 athletes, whereas Cluster 3 athletes had a significant decrease in the fraction of exhaled nitric oxide compared to pretreatment values. CONCLUSIONS: These data suggest three clusters exist in Japanese athlete population with asthma. Between the clusters, the characteristics differed with regard to symptoms, atopic features, and lower %FEV1 values. The pathogeneses between clusters may vary depending on the inflammation type and airway hyperresponsiveness.