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2.
Anticancer Res ; 40(2): 957-964, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014940

RESUMO

BACKGROUND/AIM: To describe real clinical outcomes when using systemic therapy to treat non-small cell lung cancer (NSCLC) patients who have anaplastic lymphoma kinase (ALK) fusion gene mutation. PATIENTS AND METHODS: We performed a retrospective chart review from April 2008 to March 2019 sourced from 16 medical institutes that cover a population of three million people. RESULTS: There were 129 ALK rearranged NSCLC patients. Among them, 103 patients including 40 recurrent disease cases received ALK-tyrosine kinase inhibitors (TKI) and chemotherapy. Our treatment results were comparable to previously reported clinical trials and clinical practice studies. First-line alectinib, treatment sequence of ALK-TKI followed by another ALK-TKI, and pemetrexed-containing chemotherapy contributed to the outcome of treatment. CONCLUSION: By arrangement of treatment such as treatment sequence of ALK-TKI and chemotherapy regimen, it might be possible to obtain a treatment outcome almost equivalent to those of clinical trials even in real clinical practice.

3.
COPD ; 17(1): 59-64, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31910693

RESUMO

A weighted genetic risk score (GRS) based on 16 SNPs implicated in reduced lung function in both Japanese and non-Japanese populations was previously associated with the onset of COPD and asthma. We here examine the genetic impact of this lung function GRS on specific COPD phenotypes. A cohort of Japanese COPD patients (N = 270) underwent lung function testing followed by genotyping with allele-specific arrays for 16 SNPs as well as expression quantitative trait loci at TSLP (rs2289276, rs3806933). Lung function GRS scoring and two-step cluster analyses grouped patients into different COPD phenotypes based on gender, age, smoking index, %FEV1 and lung function GRS. The genetic effect of TSLP on COPD phenotypes was also examined for interactions with the lung function GRS. A total of 270 participants were grouped into 5 clusters. The cluster with the highest levels of lung function GRS was characterized by moderate to severe airflow obstruction and the highest blood eosinophil counts. Regarding TSLP, an increased number of T alleles at both SNPs was found in the cluster characterized by moderate to severe airflow obstruction and heavy smoking (rs2289276, p value = 0.035; rs3806933, p value = 0.047) independent of the lung function GRS. A genetic susceptibility to impaired lung function carries an increased risk of developing COPD characterized by increased eosinophil counts and severe airflow obstruction while individuals with increased TSLP responses to external stimuli have an independent risk of developing severe airflow obstruction in the presence of heavy smoking.

4.
Anticancer Res ; 40(1): 413-419, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892595

RESUMO

BACKGROUND/AIM: In patients with lung cancer, there has been no study that treated 'distant metastases' as 'metastatic patterns'. This study aimed to evaluate if specific 'metastatic patterns' exist in lung cancer patients. PATIENTS AND METHODS: Data were collected from lung cancer patients between 2009 and 2018. Metastatic patterns were analyzed using cluster analysis in patients with epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma, those with small cell lung cancer (SCLC), and those with squamous cell lung cancer (SqCLC). RESULTS: In 313 patients (127 patients with EGFR mutation, 87 patients with SCLC, and 99 patients with SqCLC), metastatic patterns existed in each of the three subset groups, and metastatic patterns of these groups were statistically different. CONCLUSION: The knowledge of the metastatic patterns might be useful for clinical practice in the foreseeable future, as it enables a more efficient detection of metastatic disease through imaging, and a more effective treatment at predicted metastatic sites.


Assuntos
Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/genética , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Metástase Neoplásica , Probabilidade
5.
Anticancer Res ; 40(1): 421-426, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892596

RESUMO

BACKGROUND/AIM: Distant organ metastases do not occur at random in lung cancer. A retrospective study was conducted in order to evaluate 1) what kinds of metastatic patterns exist in three different types of lung cancer, and 2) whether metastatic patterns affected prognosis in the different types of lung cancer. PATIENTS AND METHODS: Data were collected from all consecutive patients with diagnosed lung cancer between April 2009 and October 2018 in our hospitals. Cluster analysis was performed to classify patients. Kaplan-Meier analysis, log-rank test, and Cox proportional hazards model were used. RESULTS: Epidermal growth factor-mutated adenocarcinoma, small cell lung cancer, and squamous cell lung cancer had different 'metastatic patterns', survival, and unfavorable prognostic factors, respectively. CONCLUSION: There might be different metastatic patterns, survival, and unfavorable prognostic factors in each pathological and genetic type of lung cancer. It is worthwhile carrying out diagnostic imaging and treatment considering information on metastatic patterns.


Assuntos
Neoplasias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação/genética , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida
7.
Case Rep Oncol ; 12(2): 613-620, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31543777

RESUMO

Small-cell lung cancer (SCLC) is highly sensitive to platinum-based chemotherapy. However, its indication in patients with a poor performance status (PS) at initial diagnosis is controversial. We retrospectively reviewed all clinical courses of pathologically diagnosed SCLC patients with poor PS, Eastern Cooperative Oncology Group PS 3 and 4. Among 18 patients, 12 were treated with chemotherapy and 6 with supportive care alone. During the chemotherapy courses, PS improved in 7 (58.3%, including the PS 4 cases), remained stable in 2 (16.7%), and deteriorated in 3 (25%) patients. Moreover, 5 patients showed partial responses to chemotherapy (response rate of 41.7%). Grade 3-4 neutropenia developed in 10 (83.3%) patients and grade 3 febrile neutropenia occurred in 5 (41.7%) patients, but no grade 4 non-hematological toxicity was noted. Mortality associated with lung toxicity (grade 5) due to treatment occurred in a 77-year-old-male patient with PS 3. No substantial difference in survival was observed between patients with PS 3 and 4, even when including those treated with supportive care alone. Treatment had a positive effect on survival: after chemotherapy, the 6-month survival rate of PS 3 and 4 patients was 66.7%. In contrast, all patients treated with supportive care alone died within 5 months. These findings suggest that chemotherapy is indicated in selected SCLC patients not only with PS 3, but also with PS 4.

8.
Sci Rep ; 9(1): 13159, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511572

RESUMO

A concave-shaped maximal expiratory flow-volume (MEFV) curve is a spirometric feature in chronic obstructive pulmonary disease (COPD). The MEFV curve is characterized by an increase in the Obstructive Index, which is defined as a ratio of forced vital capacity to the volume-difference between two points of half of the peak expiratory flow on the MEFV curve. We hypothesized that the Obstructive Index would reflect the severity of emphysema in patients with COPD and asthma-COPD overlap (ACO). Thus, the aim of this retrospective study was to evaluate whether the Obstructive Index on spirometry is associated with the extent of emphysema on computed tomography (CT) in patients with COPD, ACO, and asthma (N = 65, 15, and 53, respectively). The percentage of low-attenuation volume (LAV%) and wall area (WA%) were measured on CT. The Obstructive Index was higher in patients with COPD and ACO than in those with asthma. Spearman correlation showed that a greater Obstructive Index was associated with a higher LAV%, but not WA%. Multivariate analysis showed that Obstructive Index was associated with LAV% (standardized ß = 0.43, P < 0.0001) independent of other spirometric indices. The Obstructive Index is a useful spirometric index that reflects the extent of emphysema.

10.
Oncol Lett ; 18(1): 962-966, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31289575

RESUMO

We report herein a rare case of massive pleural effusion caused by papillary thyroid cancer, which was accompanied by multiple pulmonary metastasis. A 91-year-old male patient presented with shortness of breath due to massive right pleural fluid. Cytological specimens, which were obtained from pleural fluid by thoracentesis, and was consistent with that observed in surgically resected thyroid cancer 6-year previously. Immunocytochemical staining of the cells was positive for cytokeratin (CK)-7, CK-19, and positive for thyroglobulin. Massive pleural fluid due to a metastatic from papillary thyroid cancer is very rare but may develop in long-term survivors with this disease as observed in this case.

11.
In Vivo ; 33(4): 1369-1372, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31280232

RESUMO

BACKGROUND/AIM: The aim of this retrospective study was to identify, using logistic analysis, the factors associated with distant metastasis in non-small cell lung cancer patients carrying mutations in epidermal growth factor receptor. PATIENTS AND METHODS: Patients who were diagnosed with distant metastasis at the time of diagnosis up to their death and during the period from April 2009 to March 2019, were included in this study. Clinical charts and imaging studies were reviewed. RESULTS: A total of 64 patients during the research period. The factors associated with pleural metastasis were "female" and "no bone metastasis". The factor associated with brain metastasis was "lung metastasis". The factors associated with liver metastasis were "age under 70" and "Exon 19 deletion". CONCLUSION: Knowing the factors associated with distant metastasis will provide useful information to conduct targeted and efficient imaging studies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Éxons , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias
12.
J Gen Fam Med ; 20(3): 101-106, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31065474

RESUMO

Background: In patients with bronchial asthma and those with chronic obstructive pulmonary disease (COPD), inhalation therapy and rinsing of the mouth and the oropharynx by gargling ("RMOG") after inhalation are recommended. We performed a cross-sectional audit aimed at investigating (a) the proportion of patients performing "RMOG" after inhalation and (b) storage place of patients' inhaler. Methods: Patients with bronchial asthma and those with COPD were asked by medical aids at outpatient visits whether they did "RMOG every time," "RMOG sometimes," or "no RMOG" after inhalation, and where they stored their inhaler. Results: During a six month study period up to September 2017, 330 consecutive patients with asthma and those with COPD were included in the study. Two hundred and thirty-two (70.3%) of the 330 patients answered "RMOG every time" and 98 (29.7%) of them did "RMOG sometimes" and did "no RMOG." There was a difference in the proportion of patients performing RMOG after inhalation with patient age. With regard to the storage location of inhaler, we found the proportion of patients performing RMOG was higher in those who stored inhalers in a room with running water than in those who stored inhalers at other places. This difference was found in patients with both bronchial asthma and those with COPD. Conclusions: Further implementation of "patient education" on performing RMOG after inhalation for patients receiving inhaled medication is still necessary. Our results suggest that it is better to store inhalers in places where there is easy access to tap water used for RMOG.

13.
BMC Med Genet ; 20(1): 58, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940096

RESUMO

BACKGROUND: The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes. METHODS: This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters. RESULTS: In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07-1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03-1.61; P = 0.027). CONCLUSIONS: The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.


Assuntos
Idade de Início , Alelos , Asma/genética , Proteína 1 Semelhante à Quitinase-3/genética , Locos de Características Quantitativas , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Estudo de Associação Genômica Ampla , Humanos , Japão , Fenótipo
16.
Am J Respir Cell Mol Biol ; 61(4): 525-536, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30965014

RESUMO

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by peripheral airways inflammation and emphysema. Emerging evidence indicates a contribution of both innate and adaptive immune cells to the development of COPD. Transcription factor T-bet modulates the function of immune cells and therefore might be involved in the pathogenesis of COPD. To elucidate the role for T-bet in elastase-induced emphysema, pathological phenotypes were compared between wild-type and T-bet-/- mice. T-bet-/- mice demonstrated enhanced emphysema development on histological analyses, with higher values of mean linear intercept and dynamic compliance relative to wild-type mice. The number of neutrophils in BAL fluids, lung IL-6 and IL-17 expression, and the proportion of CD4+ T cells positive for IL-17 or retinoic acid receptor-related orphan receptor-γt were higher in T-bet-/- mice than in wild-type mice. Although T-bet downregulates cytokine expression in bone marrow-derived macrophages and MH-S cells, a murine alveolar cell line, depending on the surrounding environment, IL-6 expression in alveolar macrophages isolated from elastase-treated mice was not dependent on T-bet. Coculture of bone marrow-derived macrophages and CD4+ T cells revealed that T-bet regulation of IL-17 expression was dependent on CD4+ T cells. Neutralizing antibodies against IL-6R or IL-17 ameliorated the development of emphysema in T-bet-/- mice. In conclusion, we demonstrate that T-bet ameliorates elastase-induced emphysema formation by modulating the host immune response in the lungs.

17.
Respir Med Case Rep ; 26: 31-34, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30510895

RESUMO

Pasteurella multocida, which colonizes upper respiratory and digestive tracts, is a leading cause of respiratory diseases in many host species. Here, we describe a case of P. multocida pneumonia with hemoptysis. A 72-year-old female diagnosed with bronchiectasis with a 36-year history presented with a worsened infiltrative and granular shadow in the lower right lobe and lingular segment. Bronchial lavage fluid culturing suggested Pasteurella pneumonia. P. multocida was confirmed by 16S rRNA sequencing. The patient was readmitted to our hospital because of hemoptysis, and she was treated successfully with antibiotic therapy. The possibility of P. multocida infection must be considered in patients who own pets.

18.
Anticancer Drugs ; 30(1): 105-109, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30074503

RESUMO

Lung cancer is a major health concern worldwide, but new immunotherapeutic treatments for lung cancer have shown great promise and the prognosis for many severe cancers including lung cancer has been improving. In May 2017, the Food and Drug Administration approved pembrolizumab, a therapeutic antibody that blocks lymphocytic programmed death-1 (PD-1), as a first-line treatment for any solid tumor with specific genetic features. Pembrolizumab is a therapeutic antibody that blocks lymphocytic PD-1, the ligand of which (PD-L1) is expressed on tumor cells and which can prevent the immune system from recognizing and destroying tumors. Here, we report two cases of double cancer (case 1: lung and bladder cancer; case 2: gastric and lung cancer) in which pembrolizumab was effective for the treatment of both cancers in each patient.

19.
Allergol Int ; 68(1): 77-81, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30082152

RESUMO

BACKGROUND: TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations. METHODS: We performed a candidate gene case-control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations. RESULTS: A meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene-gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively. CONCLUSIONS: Our study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese.


Assuntos
Predisposição Genética para Doença , Hipersensibilidade/genética , Receptores Proteína Tirosina Quinases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipersensibilidade/epidemiologia , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adulto Jovem
20.
Free Radic Biol Med ; 129: 473-485, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30312763

RESUMO

Oxidative stress induced by cigarette smoke and other environmental pollutants contributes to refractory asthma. To better understand the role of smoking in asthma, we investigated the effects of cigarette smoke on allergic airway responses in mice and examined expression of nuclear factor-E2-related factor-2 (Nrf2) and its downstream factors, because Nrf2 is known to play a pivotal role in antioxidant responses. OVA-sensitized and challenged BALB/c mice were exposed to cigarette smoke and then treated with dexamethasone, sulforaphane (an activator of Nrf2), or their combination. Upon exposure to cigarette smoke, Nrf2 and associated transcripts were upregulated in response to oxidative stress, and asthmatic responses were steroid resistant. In OVA-sensitized and challenged mice exposed to cigarette smoke and treated with sulforaphane, Nrf2-mediated antioxidant responses were upregulated to a greater extent, and steroid sensitivity of asthmatic responses was restored. Moreover, the expression and activity of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness, was reduced in mice exposed to cigarette smoke, but restored by sulforaphane treatment. No effects of sulforaphane were observed in Nrf2-deficient mice. These findings indicate that cigarette smoke induces steroid unresponsiveness in asthmatic airways, and that sulforaphane restores steroid sensitivity via upregulation of Nrf2 and enhancement of HDAC2 expression and activity. Thus, Nrf2 may serve as a potential molecular target for cigarette smoke-related refractory asthma resistant to steroid therapy.


Assuntos
Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Dexametasona/farmacologia , Histona Desacetilase 2/genética , Isotiocianatos/farmacologia , Fator 1 Nuclear Respiratório/genética , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Asma/etiologia , Asma/genética , Asma/metabolismo , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Regulação da Expressão Gênica , Histona Desacetilase 2/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Fator 1 Nuclear Respiratório/agonistas , Fator 1 Nuclear Respiratório/metabolismo , Ovalbumina/administração & dosagem , Estresse Oxidativo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Tabaco/efeitos adversos , Tabaco/química
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