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1.
Biol Pharm Bull ; 47(2): 361-365, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38311396

RESUMEN

Immune-related adverse events (irAEs) affect all organs and are associated with various symptoms. The identification of biomarkers that can predict irAEs may be particularly clinically useful. This study aimed to investigate whether the prognostic nutritional index (PNI) before the initiation of immune checkpoint inhibitor (ICI) treatment can predict the occurrence of irAEs. We conducted a survey of 111 patients with cancer who were receiving ICI fixed-dose monotherapy at Saga University Hospital from the time each ICI became available until January 2020. We compared the PNI between the patients with and without irAE expression, established a cutoff value for PNI associated with the development of irAEs, and investigated the incidence of irAEs and progression-free survival (PFS) in groups divided by the cutoff value. Patients with irAEs had significantly higher PNI than did those without, and there was a significant association between PNI and irAEs after adjusting for potential factors (odds ratio, 1.12; 95% confidence interval, 1.03-1.21). In addition, PNI ≥44.2 was associated with a significantly higher incidence of irAEs (75.0% vs. 35.2%, p = 0.0001) and significantly longer PFS than PNI <44.2 (p = 0.025). In conclusion, pretreatment PNI may be associated with the risk of developing irAEs in patients with advanced recurrent solid tumors. When the PNI is ≥44.2, patient management is important for avoiding serious AEs because while the treatment may be effective, the occurrence of irAEs is a concern.


Asunto(s)
Enfermedades del Sistema Inmune , Neoplasias , Humanos , Evaluación Nutricional , Pronóstico , Neoplasias/tratamiento farmacológico , Biomarcadores , Inmunoterapia/efectos adversos , Estudios Retrospectivos
2.
Allergol Int ; 73(2): 313-322, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38145912

RESUMEN

BACKGROUND: Ozone is one of the triggers of asthma, but its impact on the pathophysiology of asthma, such as via airway inflammation and airway hyperresponsiveness (AHR), is not fully understood. Thymic stromal lymphopoietin (TSLP) is increasingly seen as a crucial molecule associated with asthma severity, such as corticosteroid resistance. METHODS: Female BALB/c mice sensitized and challenged with house dust mite (HDM) were exposed to ozone at 2 ppm for 3 h. Airway inflammation was assessed by the presence of inflammatory cells in bronchoalveolar lavage fluid and concentrations of cytokines including TSLP in lung. Anti-TSLP antibody was administered to mice to block the signal. Survival and adhesion of bone marrow-derived eosinophils in response to granulocyte colony-stimulating factor (G-CSF) were evaluated. RESULTS: Ozone exposure increased eosinophilic airway inflammation and AHR in mice sensitized and challenged with HDM. In addition, TSLP, but not IL-33 and IL-25, was increased in lung by ozone exposure. To confirm whether TSLP signaling is associated with airway responses to ozone, an anti-TSLP antibody was administered, and it significantly attenuated eosinophilic airway inflammation, but not AHR. Interestingly, G-CSF, but not type 2 cytokines such as IL-4, IL-5, and IL-13, was regulated by TSLP signaling associated with eosinophilic airway inflammation, and G-CSF prolonged survival and activated eosinophil adhesion. CONCLUSIONS: The present data show that TSLP contributes to ozone-induced exacerbations of eosinophilic airway inflammation and provide greater understanding of ozone-induced severity mechanisms in the pathophysiology of asthma related to TSLP and G-CSF.


Asunto(s)
Asma , Linfopoyetina del Estroma Tímico , Animales , Femenino , Ratones , Citocinas , Factor Estimulante de Colonias de Granulocitos , Inflamación , Ratones Endogámicos BALB C
3.
Respir Investig ; 61(6): 698-701, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37708635

RESUMEN

A patient with sarcoidosis was found to have a massive left pleural effusion. Her chest computed tomography showed small nodules in the lung parenchyma and swelling of the hilar lymph nodes, with normal visceral and parietal pleura. Thoracoscopy showed white nodules on the visceral pleura and normal parietal pleura, which were resected. Epithelioid granulomas were seen in the visceral pleura and lung parenchyma. Surprisingly, in the parietal pleura, abnormal cells that were positive for the leukocyte common antigen, CD20, and CD79a were found, leading to the diagnosis of malignant B-cell lymphoma.


Asunto(s)
Linfoma , Derrame Pleural , Neoplasias Pleurales , Sarcoidosis , Femenino , Humanos , Pleura/diagnóstico por imagen , Neoplasias Pleurales/complicaciones , Neoplasias Pleurales/diagnóstico por imagen , Sarcoidosis/complicaciones , Sarcoidosis/diagnóstico por imagen , Linfoma/patología
4.
Chest ; 163(6): e286, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37295890
5.
Oncol Lett ; 25(5): 180, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37033099

RESUMEN

Prospective studies on risk factors for the occurrence of venous thromboembolism (VTE) in Asian patients with cancer are limited. Therefore, the present study assessed risk factors for VTE, including multiple blood biomarkers and risk scores consisting of several risk factors, in Japanese patients receiving anticancer drug therapy. In this single-center, prospective, observational study, 200 patients with six types of cancer were enrolled and followed for 1 year to observe the occurrence of symptomatic or asymptomatic VTE. The present study evaluated risk factors, Khorana and Vienna cancer and thrombosis study (CATS) scores at enrollment, and longitudinal data on various blood biomarkers. A Vienna CATS score of ≥3 was significantly associated with VTE occurrence (HR, 2.8; 95% CI, 0.9-8.7; P=0.045). In multivariable analysis, there was a significant association between VTE and the presence of pancreatic cancer (HR, 3.2; 95% CI, 1.1-8.8; P=0.028) and high soluble fibrin (HR, 3.7; 95% CI, 1.1-7.8; P=0.036). Covariate analysis using the propensity score also showed a significant association with hemoglobin dichotomized at <100 g/l (HR, 3.9; 95% CI, 1.1-14.0; P=0.034). Longitudinal data indicated that VTE was associated with soluble fibrin baseline values and an increase in D-dimer levels over time. The present results suggested that blood biomarkers are beneficial for predicting the risk of VTE in Japanese patients with cancer. The present study also provided novel evidence for the importance of measuring soluble fibrin in patients with cancer.

6.
J Neurol ; 270(7): 3413-3423, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36939931

RESUMEN

OBJECTIVE: The purpose of this study is to report the clinical characteristics of dysautonomia associated with immune checkpoint inhibitors (ICIs). METHODS: We reported two patients with autoimmune autonomic ganglionopathy (AAG) occurring as immune-related adverse events (irAEs). We also performed a review of previous case reports presenting dysautonomia during ICI therapy. Moreover, we conducted pharmacovigilance analyses using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to investigate dysautonomia associated with ICI. RESULTS: Two patients in our care developed both AAG and autoimmune encephalitis following ICI therapy for lung cancers. We comprehensively reviewed 13 published cases (M:F = 11:2, mean onset age of 53 years) with ICI-associated dysautonomia including AAG (n = 3) and autonomic neuropathy (n = 10). Of these, ICI monotherapy was performed in seven and combination ICI use in six. In 6 of 13 patients, dysautonomia appeared within one month after the start of ICIs. Orthostatic hypotension was observed in 7 and urinary incontinence or retention in five. All patients except three showed gastrointestinal symptoms. Anti-ganglionic acetylcholine receptor antibodies were undetectable. All but two patients received immune-modulating therapy. Immuno-modulating therapy was effective in three patients with AAG and two patients with autonomic neuropathy, but ineffective in the others. Five patients died, of either the neurological irAE (n = 3) or cancer (n = 2). The pharmacovigilance analyses using FAERS showed that ipilimumab monotherapy and the combination of nivolumab and ipilimumab constituted significant risks for developing dysautonomia, consistent with the review of literature. CONCLUSION: ICIs can cause dysautonomia including AAG, and autonomic neuropathy is a neurological irAE.


Asunto(s)
Enfermedades Autoinmunes , Neoplasias Pulmonares , Enfermedades del Sistema Nervioso , Disautonomías Primarias , Humanos , Persona de Mediana Edad , Ipilimumab/efectos adversos , Inhibidores de Puntos de Control Inmunológico , Nivolumab/efectos adversos , Enfermedades del Sistema Nervioso/inducido químicamente , Disautonomías Primarias/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Autoanticuerpos , Enfermedades Autoinmunes/tratamiento farmacológico
7.
Artículo en Inglés | MEDLINE | ID: mdl-36767227

RESUMEN

INTRODUCTION: Obesity is associated with severe asthma, but no specific treatment has been established. The gut microbiome is increasingly recognized as a crucial factor, but specific treatments focused on the gut microbiome have not been established. Recently, azithromycin has been found to have the capacity to attenuate exacerbations, a characteristic of severe asthma. The effect of azithromycin on obesity-induced severe asthma is not understood. METHODS: The purpose of the present study is to clarify the effect of azithromycin on exacerbations in asthmatic patients with obesity. To explore the mechanism, the gut microbiome, metabolites of microbes such as short-chain fatty acids, and blood inflammatory cytokines will be analyzed to evaluate the correlation with the effect of azithromycin on exacerbations in obesity-induced severe asthma. A multi-center, prospective, single-arm intervention study is planned. DISCUSSION: The present study will allow us to evaluate the effect of azithromycin on exacerbations, particularly in asthma patients with obesity, and explore biomarkers, targeting molecules including the gut microbiome, which are correlated with decreased exacerbations. The present results could contribute to identifying new therapeutic prospects and targeted microbes or molecules associated with severe clinical characteristics in asthmatic patients with obesity. TRIAL REGISTRATION: This study has been registered as a prospective study with the University Hospital Medical Information Network (UMIN0000484389) and the Japan Registry of Clinical Trials (jRCTs071220023).


Asunto(s)
Asma , Azitromicina , Humanos , Azitromicina/uso terapéutico , Estudios Prospectivos , Método Doble Ciego , Asma/tratamiento farmacológico , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Antibacterianos/uso terapéutico , Estudios Multicéntricos como Asunto
8.
BMC Cancer ; 23(1): 77, 2023 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-36690964

RESUMEN

BACKGROUND: Precision medicine with gene panel testing based on next-generation sequencing for patients with cancer is being used increasingly in clinical practice. HER2, which encodes the human epidermal growth factor receptor 2 (HER2), is a potentially important driver gene. However, therapeutic strategies aimed at mutations in the HER2 extracellular domain have not been clarified. We therefore investigated the effect of EGFR co-targeted therapy with HER2 on patient-derived cancer models with the HER2 extracellular domain mutation E401G, based on our previous findings that this mutation has an epidermal growth factor receptor (EGFR)-mediated activation mechanism. METHODS: We generated a xenograft (PDX) and a cancer tissue-originated spheroid (CTOS) from a patient's cancer containing an amplified HER2 E401G mutation. With these platforms, we compared the efficacy of afatinib, a tyrosine kinase inhibitor having anti-HER2 and anti-EGFR activity, with two other therapeutic options: lapatinib, which has similar properties but weaker EGFR inhibition, and trastuzumab plus pertuzumab, for which evidence exists of treatment efficacy against cancers with wild-type HER2 amplification. Similar experiments were also performed with H2170, a cell line with wild-type HER2 amplification, to contrast the characteristics of these drug's efficacies against HER2 E401G. RESULTS: We confirmed that PDX and CTOS retained morphological and immunohistochemical characteristics and HER2 gene profiles of the original tumor. In both PDX and CTOS, afatinib reduced tumor size more than lapatinib or trastuzumab plus pertuzumab. In addition, afatinib treatment resulted in a statistically significant reduction in HER2 copy number at the end of treatment. On the other hand, in H2170 xenografts with wild-type HER2 amplification, trastuzumab plus pertuzumab was most effective. CONCLUSIONS: Afatinib, a dual inhibitor of HER2 and EGFR, showed a promising effect on cancers with amplified HER2 E401G, which have an EGFR-mediated activation mechanism. Analysis of the activation mechanisms of mutations and development of therapeutic strategies based on those mechanisms are critical in precision medicine for cancer patients.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Afatinib , Lapatinib , Antineoplásicos/uso terapéutico , Receptor ErbB-2/metabolismo , Trastuzumab , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Mutación , Línea Celular Tumoral , Receptores ErbB/genética
9.
Chest ; 163(1): e7-e11, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36628691

RESUMEN

CASE PRESENTATION: A 45-year-old Japanese woman was diagnosed with anemia in a work place medical check-up and came to our hospital for further investigations. She had experienced general fatigue and orthostatic dizziness for 6 months without fever or respiratory symptoms, including cough, sputum, hemoptysis, or dyspnea. She had undergone annual medical check-ups previously, which had shown no abnormalities, including anemia. She had no history of weight loss, epimenorrhagia, hematuria, or melena. She had no significant positive medical history and was not on any regular medication or supplements. She had no history of alcohol abuse or smoking.


Asunto(s)
Anemia Ferropénica , Femenino , Humanos , Persona de Mediana Edad , Anemia Ferropénica/diagnóstico , Anemia Ferropénica/etiología , Hemoptisis , Disnea/diagnóstico , Disnea/etiología , Tos , Esputo , Diagnóstico Diferencial
10.
Cancer Sci ; 114(3): 1045-1055, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36382532

RESUMEN

Treatment efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is diverse even in non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. Extraordinary long-term responses sustained over 3 years among NSCLC patients treated with afatinib, an EGFR-TKI, have been reported, but how to predict such long survivors has not been clarified. A multi-institutional prospective observational study, based on comprehensive genomic examination performed with next-generation sequencing of circulating tumor DNA (ctDNA), was conducted to identify potential predictive markers of long-term response to afatinib. Twenty-nine patients with advanced stage NSCLC and EGFR driver mutations detected by standard techniques were enrolled in the study. ctDNA from plasma collected before afatinib treatment was analyzed by Guardant360. ctDNA was detected in 25 of the 29 samples. Median progression-free survival was shorter in patients whose tumors had EGFR copy number gain (7.0 vs 23.0 months, p = 0.022). The impact of EGFR copy number on cell proliferation and the antitumor effect of afatinib were evaluated using genome-editing lung cancer cell lines. HCC827 with EGFR amplification was relatively resistant to afatinib at concentrations below 0.5 nM, but genome-edited derivatives of HCC827 with decreased EGFR copy number demonstrated growth inhibition with 0.1 nM afatinib. The absence of EGFR copy number gain detected in ctDNA may be a predictive marker of long-term response to afatinib. Comprehensive genomic analysis could lead to a more accurate prediction of EGFR-TKI efficacy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Afatinib , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/patología , Variaciones en el Número de Copia de ADN , Inhibidores de Proteínas Quinasas/farmacología , Receptores ErbB/genética , Mutación
11.
Thorac Cancer ; 13(24): 3459-3466, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36263938

RESUMEN

BACKGROUND: Transbronchial biopsy (TBB) with endobronchial ultrasonography and a guide sheath (EBUS-GS) is an effective examination tool for the diagnosis of lung cancer. Factors related to making the diagnosis are still not fully understood. METHODS: A total of 367 patients who underwent EBUS-GS and were diagnosed with lung cancer in Saga University Hospital were investigated retrospectively. Clinical characteristics were compared between 244 patients who were diagnosed with lung cancer and 123 patients who were not diagnosed by TBB with EBUS-GS but were diagnosed by other examinations. RESULTS: Size of target lesion, rate of patients with target lesion size ≥20 mm, presence of the bronchus sign, and detection by EBUS imaging were significantly associated with making the diagnosis (all p < 0.01). In patients whose lesion was detected by EBUS imaging, patients with positive findings within the lesion were significantly more often diagnosed by TBB with EBUS-GS than those with positive findings adjacent to the lesion (p < 0.01). The odds ratio (OR) of patients whose lesion was detected by EBUS imaging (OR [95% confidence interval] 14.5 [8.0-26.4]) tended to be higher compared to the ORs of size of lesion ≥20 mm (3.9 [2.2-6.8]) and the bronchus sign (7.5 [4.6-12.2]). CONCLUSION: Targeted lesion diameter ≥20 mm, bronchus sign, and detection by EBUS imaging, especially within the lesion, are important factors for the diagnosis of lung cancer by TBB with EBUS-GS.


Asunto(s)
Broncoscopía , Neoplasias Pulmonares , Humanos , Broncoscopía/métodos , Estudios Retrospectivos , Endosonografía/métodos , Biopsia/métodos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología
12.
JTO Clin Res Rep ; 3(11): 100404, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36275911

RESUMEN

Introduction: Pembrolizumab is a programmed death-ligand 1 inhibitor that was initially indicated for monotherapy in patients with advanced lung cancer. The Japanese Lung Cancer Society conducted an observational study on pembrolizumab using confirmative data obtained through postmarketing all-case surveillance (PMACS), which was performed by a pharmaceutical company under the Japanese law in 2017. Methods: This multicenter observational study was conducted by the Japanese Lung Cancer Society using PMACS data with the newly created central registration system regarding patients with NSCLC who received pembrolizumab monotherapy between February 1, 2017 and June 30, 2017; a new database was created by adding the clinical information regarding prognosis for 3 years after therapy to the existing data collected by PMACS. Results: A total of 300 patients from 43 facilities were enrolled in this study. The median overall survival and progression-free survival after pembrolizumab initiation were 558 and 188 days, respectively. Moreover, the 1- and 3-year survival rates were 58.9% and 33.7%, respectively. Results of multivariate analysis revealed performance status (p < 0.0001), histology (p = 0.0118), previous chemotherapy (p = 0.0007), programmed death-ligand 1 expression status (p = 0.0195), and previous steroid use (p = 0.0460) as significant factors that affected overall survival. The toxicity profile was similar to that previously reported. Conclusions: In this first attempt to use PMACS data, we successfully collected clinical information and found the real-world efficacy and safety of pembrolizumab.

13.
Sci Rep ; 12(1): 16457, 2022 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-36180514

RESUMEN

Obesity is associated with the severity of asthma, which is characterized by airway obstruction. Pulmonary function testing is one of the important examinations for evaluating airway obstruction. However, the impact of obesity on pulmonary function in patients with asthma is not fully understood. A total of 193 patients with asthma and 2159 patients without asthma who visited Saga University Hospital were investigated retrospectively. Obesity was defined as a body mass index (BMI) greater than 25 kg/m2. Pulmonary functions including forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were compared between patients with and without asthma, focusing especially on obesity. FVC percent predicted and FEV1 percent predicted were significantly lower in patients with asthma than in those without asthma (p = 0.03, < 0.01 respectively). In patients with asthma, FVC percent predicted and FEV1 percent predicted were significantly lower in patients with obesity than in those without obesity (all p < 0.01). In addition, BMI was negatively correlated with FEV1 (r =- 0.21, p = 0.003) and FVC (r = - 0.15, p = 0.04), along with the percent predicted. On multivariate analysis in patients with asthma, FVC (ß [95% confidence interval] 0.12 [0.02-0.22], p = 0.02) and FEV1 (0.13 [0.05-0.22], p < 0.01) were still significantly different between patients with and without obesity. However, these obesity-associated differences were not observed in patients without asthma. Obesity reduces pulmonary function, including FVC and FEV1, in patients with asthma, but not in those without asthma.


Asunto(s)
Obstrucción de las Vías Aéreas , Asma , Adulto , Asma/complicaciones , Volumen Espiratorio Forzado , Humanos , Japón/epidemiología , Obesidad/complicaciones , Estudios Retrospectivos , Capacidad Vital
14.
PLoS One ; 17(3): e0266112, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35358259

RESUMEN

INTRODUCTION: Clinical sequencing has provided molecular and therapeutic insights into the field of clinical oncology. However, despite its significance, its clinical utility in Japanese patients remains unknown. Here, we examined the clinical utility of tissue-based clinical sequencing with FoundationOne® CDx and FoundationOne® Heme. Between August 2018 and August 2019, 130 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne® CDx or FoundationOne® Heme. RESULTS: The median age of 130 patients was 60.5 years (range: 3 to 84 years), and among them, 64 were males and 66 were females. Major cancer types were gastrointestinal cancer (23 cases) and hepatic, biliary, and pancreatic cancer (21 cases). A molecular tumor board had been completed on all 130 cases by October 31, 2019. The median number of gene alterations detected by Foundation testing, excluding variants of unknown significance (VUS) was 4 (ranged 0 to 21) per case. Of the 130 cases, one or more alterations were found in 123 cases (94.6%), and in 114 cases (87.7%), actionable alterations with candidates for therapeutic agents were found. In 29 (22.3%) of them, treatment corresponding to the gene alteration was performed. Regarding secondary findings, 13 cases (10%) had an alteration suspected of a hereditary tumor. Of the 13 cases, only one case received a definite diagnosis of hereditary tumor. CONCLUSIONS: Our study showed that clinical sequencing might be useful for detecting gene alterations in various cancer types and exploring treatment options. However, many issues still need to be improved.


Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias Pancreáticas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Niño , Preescolar , Femenino , Hemo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Japón , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Pancreáticas/genética , Adulto Joven
15.
J Asthma Allergy ; 15: 169-177, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35177908

RESUMEN

PURPOSE: Idiopathic chronic eosinophilic pneumonia (ICEP) is a rare, chronic respiratory disease. Corticosteroid therapy is effective for ICEP, but relapse is frequent after its tapering, which leads to chronic use and corticosteroid-related adverse effects. Currently, biological agents targeting interleukin 5 (IL-5) are considered alternatives for treating ICEP patients with frequent relapse, but the detailed effects are not fully understood. PATIENTS AND METHODS: The clinical characteristics of 30 patients with ICEP, especially 12 patients with ICEP who experienced relapse after corticosteroid dose tapering, were evaluated retrospectively. In addition, 4 ICEP patients with frequent relapse treated by IL-5-targeted biological agents were reviewed. RESULTS: Of the 30 patients diagnosed with ICEP, 12 patients (40.0%) recurred after corticosteroid dose tapering, and 9 (30.0%) were treated with maintenance doses of corticosteroid. Of ICEP patients who experienced recurrence, 6 (50.0%) had frequent relapses (2 or more times). All 4 patients treated with anti-IL-5 agents had their corticosteroid dose reduced without any relapses; in 3 patients, corticosteroids were withdrawn. CONCLUSION: Anti-IL-5 agents might be alternatives for treating ICEP patients with frequent relapses.

16.
Cell Oncol (Dordr) ; 45(1): 121-134, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34997908

RESUMEN

PURPOSE: Dealing with variants of unknown significance (VUS) is an important issue in the clinical application of NGS-based cancer gene panel tests. We detected a novel ERBB2 extracellular domain VUS, c.1157A > G p.(E401G), in a cancer gene panel test. Since the mechanisms of activation by ERBB2 extracellular domain (ECD) variants are not fully understood, we aimed to clarify those mechanisms and the biological functions of ERBB2 E401G. METHODS: ERBB2 E401G was selected as VUS for analysis because multiple software tools predicted its pathogenicity. We prepared ERBB2 expression vectors with the E401G variant as well as vectors with S310F and E321G, which are known to be activating mutations. On the basis of wild-type ERBB2 or mutant ERBB2 expression in cell lines without ERBB2 amplification or variants, we evaluated the phosphorylation of human epidermal growth factor receptor 2 and related proteins, and investigated with molecular dynamics (MD) simulation the mechanisms conferred by the variants. The biological effects of ERBB2 E401G were also investigated, both in vitro and in vivo. RESULTS: We found that ERBB2 E401G enhances C-terminal phosphorylation in a way similar to S310F. MD simulation analysis revealed that these variants maintain the stability of the EGFR-HER2 heterodimer in a ligand-independent manner. Moreover, ERBB2 E401G-transduced cells showed an increased invasive capacity in vitro and an increased tumor growth capacity in vivo. CONCLUSION: Our results provide important information on the activating mechanisms of ERBB2 extracellular domain (ECD) variants and illustrate a model workflow integrating wet and dry bench processes for the analysis of VUS detected with cancer gene panel tests.


Asunto(s)
Neoplasias , Receptor ErbB-2 , Humanos , Mutación/genética , Neoplasias/genética , Oncogenes , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
17.
Int J Chron Obstruct Pulmon Dis ; 16: 3297-3307, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34908832

RESUMEN

BACKGROUND: Prolonged sedentary behavior is associated with worse prognosis in patients with chronic obstructive pulmonary disease (COPD). Our previous study found that first-line dual therapy with tiotropium/olodaterol significantly reduces sedentary time compared to tiotropium monotherapy in Japanese patients with treatment-naïve COPD, although the characteristics of responders to dual-therapy versus monotherapy for COPD are still unclear. METHODS: Patients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Physical activity was assessed using a triaxle accelerometer for 2 weeks before and after treatment. This analysis focused on the change in sedentary time, indicated by physical activity of 1.0-1.5 metabolic equivalents (METs), with stratification for the following factors: age, body mass index (BMI), pulmonary function, COPD assessment test (CAT), the 6-minute walk distance (6MWD), and physical activity level at study entry. RESULTS: Thirty-five patients received tiotropium/olodaterol and 34 patients received tiotropium. In patients with lower inspiratory capacity at study entry, a significant reduction in sedentary time was observed in the tiotropium/olodaterol group compared with the tiotropium group (Tio: -12.8 ± 13.5 min, Tio/Olo: -65.1 ± 21.0 min, mean difference, -52.2 min, 95% CI -103.6 to 0.88, p = 0.046). In patients with a shorter duration of physical activity of ≥2 METs at study entry, a significant reduction of sedentary time was observed in the tiotropium/olodaterol group compared with the tiotropium group (Tio: -3.3 ± 17.5 min, Tio/Olo: -72.9 ± 23.1 min, mean difference, -69.7 min, 95% CI -128.7 to -10.6, p = 0.02). There were no differences in terms of age, BMI, CAT score, 6MWD, FEV1, FVC, VC, and physical activity of 1.0-1.5 METs and ≥3.0 METs. CONCLUSION: This study showed that COPD patients with lower inspiratory capacity or shorter active time of ≥2.0 METs at study entry are likely to exhibit significantly greater reduction in sedentary time with tiotropium/olodaterol treatment.


Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica , Conducta Sedentaria , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Benzoxazinas/efectos adversos , Broncodilatadores/efectos adversos , Combinación de Medicamentos , Volumen Espiratorio Forzado , Humanos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Bromuro de Tiotropio/efectos adversos , Resultado del Tratamiento
19.
Sci Rep ; 11(1): 15862, 2021 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-34354171

RESUMEN

Decreasing exercise tolerance is one of the key features related to a poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cardiopulmonary exercise testing (CPET) is useful for evaluating exercise tolerance. The present study was performed to clarify the correlation between exercise tolerance and clinical parameters, focusing especially on the cross-sectional area (CSA) of skeletal muscle. The present study investigated 69 patients with COPD who underwent CPET. The correlations between oxygen uptake ([Formula: see text]) at peak exercise and clinical parameters of COPD, including skeletal muscle area measured using single-section axial computed tomography (CT), were evaluated. The COPD assessment test score (ρ = - 0.35, p = 0.02) was weakly correlated with [Formula: see text] at peak exercise. In addition, forced expiratory volume in one second (FEV1) (ρ = 0.39, p = 0.0009), FEV1/forced vital capacity (ρ = 0.33, p = 0.006), and the CSA of the pectoralis muscles (PMs) (ρ = 0.36, p = 0.007) and erector spinae muscles (ECMs) (ρ = 0.39, p = 0.003) were correlated with [Formula: see text] at peak exercise. Multivariate analysis adjusted by age and FEV1 indicated that PMCSA was weakly correlated after adjustment (ß value [95% confidence interval] 0.175 [0.03-0.319], p = 0.02). In addition, ECMCSA tended to be correlated, but not significantly after adjustment (0.192 [- 0.001-0.385] p = 0.052). The COPD assessment test, FEV1, FEV1/FVC, PMCSA, and ECMCSA were significantly correlated with [Formula: see text] at peak exercise.


Asunto(s)
Tolerancia al Ejercicio/fisiología , Músculo Esquelético/patología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Anciano , Anciano de 80 o más Años , Prueba de Esfuerzo/métodos , Femenino , Volumen Espiratorio Forzado/fisiología , Humanos , Japón , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Oxígeno/metabolismo , Consumo de Oxígeno/fisiología , Músculos Pectorales/patología , Ventilación Pulmonar/fisiología , Respiración , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad , Capacidad Vital/fisiología
20.
Respir Med Case Rep ; 33: 101430, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34401274

RESUMEN

A 37-year-old man with fever, cough, and dyspnea with no medical history developed an eosinophilic pleural effusion and blood eosinophilia. No evidence of malignancy or pathogens was detected in the pleural effusion, and the pleural specimen obtained by thoracoscopy showed eosinophilic infiltration with inflammatory granulation tissue without fibrinoid necrosis or malignant cells. Since a myeloproliferative disorder was also excluded, the diagnosis was idiopathic eosinophilic pleurisy. Corticosteroid treatment was started and then slowly tapered, and the eosinophilic pleural effusion resolved. Considering the various etiologies of eosinophilic pleurisy, a practical clinical approach to the investigation and diagnosis of eosinophilic pleurisy is presented.

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