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OBJECTIVES: We investigated the occurrence of non-respiratory bacterial and fungal secondary infections, causative organisms, impact on clinical outcomes, and association between the secondary pathogens and mortality in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: This was a retrospective cohort study that included data from inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021). We obtained demographic, epidemiological, and microbiological data throughout the course of hospitalization and analyzed the cases of COVID-19 complicated by non-respiratory bacterial infections. RESULTS: Of the 1914 patients included, non-respiratory bacterial infections with COVID-19 were diagnosed in 81 patients (4.2%). Of these, 59 (3.1%) were secondary infections. Bacteremia was the most frequent bacterial infection, occurring in 33 cases (55.9%), followed by urinary tract infections in 16 cases (27.1%). Staphylococcus epidermidis was the most common causative organism of bacteremia. Patients with COVID-19 with non-respiratory secondary bacterial infections had significantly higher mortality, and a multivariate logistic regression analysis demonstrated that those with bacteremia (aOdds Ratio = 15.3 [5.97-39.1]) were at higher risk of death. Multivariate logistic regression analysis showed that age, male sex, use of steroids to treat COVID-19, and intensive care unit admission increased the risk for nosocomial bacteremia. CONCLUSIONS: Secondary bacteremia is an important complication that may lead to poor prognosis in cases with COVID-19. An appropriate medical management strategy must be established, especially for patients with concomitant predisposing factors.
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Bacteriemia , Infecciones Bacterianas , COVID-19 , Coinfección , Micosis , Humanos , Masculino , COVID-19/complicaciones , COVID-19/epidemiología , Estudios Retrospectivos , Coinfección/epidemiología , Bacteriemia/tratamiento farmacológico , Bacteriemia/epidemiología , Bacteriemia/microbiología , Infecciones Bacterianas/microbiología , Micosis/microbiología , Prueba de COVID-19RESUMEN
BACKGROUND: Although cases of respiratory bacterial infections associated with coronavirus disease 2019 (COVID-19) have often been reported, their impact on the clinical course remains unclear. Herein, we evaluated and analyzed the complication rates of bacterial infections, causative organisms, patient backgrounds, and clinical outcome in Japanese patients with COVID-19. METHODS: We performed a retrospective cohort study that included inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021) and obtained demographic, epidemiological, and microbiological results and the clinical course and analyzed the cases of COVID-19 complicated by respiratory bacterial infections. RESULTS: Of the 1,863 patients with COVID-19 included in the analysis, 140 (7.5%) had respiratory bacterial infections. Community-acquired co-infection at COVID-19 diagnosis was uncommon (55/1,863, 3.0%) and was mainly caused by Staphylococcus aureus, Klebsiella pneumoniae and Streptococcus pneumoniae. Hospital-acquired bacterial secondary infections, mostly caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were diagnosed in 86 patients (4.6%). Severity-associated comorbidities were frequently observed in hospital-acquired secondary infection cases, including hypertension, diabetes, and chronic kidney disease. The study results suggest that the neutrophil-lymphocyte ratio (> 5.28) may be useful in diagnosing complications of respiratory bacterial infections. COVID-19 patients with community-acquired or hospital-acquired secondary infections had significantly increased mortality. CONCLUSIONS: Respiratory bacterial co-infections and secondary infections are uncommon in patients with COVID-19 but may worsen outcomes. Assessment of bacterial complications is important in hospitalized patients with COVID-19, and the study findings are meaningful for the appropriate use of antimicrobial agents and management strategies.
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Infecciones Bacterianas , COVID-19 , Coinfección , Infecciones Comunitarias Adquiridas , Infección Hospitalaria , Infecciones del Sistema Respiratorio , Infecciones Estafilocócicas , Humanos , COVID-19/complicaciones , COVID-19/epidemiología , SARS-CoV-2 , Estudios Retrospectivos , Coinfección/epidemiología , Prueba de COVID-19 , Pueblos del Este de Asia , Infecciones Bacterianas/epidemiología , Infecciones Bacterianas/microbiología , Infecciones del Sistema Respiratorio/epidemiología , Infecciones Comunitarias Adquiridas/epidemiología , Progresión de la EnfermedadRESUMEN
INTRODUCTION: Cisplatin-based chemotherapy was established in the 1980s, and it has been improved by the development of a short hydration protocol in lung cancer therapy. However, cisplatin-based chemotherapy is still associated with renal toxicity. Because 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC) is known to be a mitochondrial activator and a heme oxygenase-1 (HO-1) inducer, 5-ALA with SFC is speculated to mitigate cisplatin-induced renal inflammation. METHODS: We investigated the effects of oral administration of 5-ALA with SFC for preventing cisplatin-based nephrotoxicity in patients with lung cancer and evaluated its benefits for patients who received cisplatin-based chemotherapy. The primary endpoint was the significance of the difference between the serum creatinine (sCr) levels of the patients administered 5-ALA with SFC and those given placebo after course 1 of chemotherapy. The difference in the estimated glomerular filtration rate (eGFR) between the two groups was also evaluated as the secondary endpoint. RESULTS: The double-blind, randomized two-arm studies were conducted at 15 medical facilities in Japan; 54 male and 20 female patients with lung cancer who received cisplatin-based chemotherapy between the ages of 42 and 75 years were included in the study. The compliance rate was greater than 94% in the primary assessment and subsequent drug administration periods. All enrolled patients completed the four cycles of cisplatin-based chemotherapy with short hydration. The average level of sCr on day 22 of course 1 was 0.707 mg/dL in the group treated with 5-ALA and SFC and 0.735 mg/dL in the placebo group, respectively, and the sCr in the test group was significantly lower than that in the placebo group (p = 0.038). In addition, the eGFR was significantly higher in the SPP-003 group than in the placebo group up to day 1 of course 3 (84.66 and 75.68 mL/min/1.73 m2, respectively, p = 0.02) and kept better even after the last administration of the study drug (82.37 and 73.49 mL/min/1.73 m2, respectively, p = 0.013). CONCLUSIONS: The oral administration of 5-ALA with SFC is beneficial to patients undergoing cisplatin-based chemotherapy for lung cancer with short hydration.
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Ácido Aminolevulínico , Neoplasias Pulmonares , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Ácido Aminolevulínico/uso terapéutico , Ácido Aminolevulínico/farmacología , Cisplatino , Ácido Cítrico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Paradoxical reactions (PRs) to antituberculosis (anti-TB) drugs during treatment are well known phenomena, but a PR presenting as a new pulmonary lesion after completion of treatment is extremely rare, and little is known about the management of such cases. A 44-year-old man was diagnosed with pulmonary TB. His sputum cultures became negative 45 days after the initiation of standard anti-TB treatment. Upon the patient's completion of 6 months of anti-TB therapy, computed tomography revealed a new irregularly shaped mass in the lower left pulmonary lobe. A transbronchial lung biopsy (TBLB) revealed caseous necrosis and granulomatosis surrounded by epithelioid and multinucleated giant cells. Cultures of both the TBLB specimen and bronchoalveolar lavage fluid remained negative for TB. The CT shadow disappeared 6 months later without further administration of anti-TB drugs. Careful observation without therapy may be sufficient for a patient treated for TB who develops a PR upon completion of treatment, if the patient has achieved a bacteriological remission.
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Antituberculosos/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/patología , Adulto , Biopsia/métodos , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , MasculinoRESUMEN
OBJECTIVE: To evaluate the value of the interferon-gamma release assays and low-dose computed tomography for the pulmonary tuberculosis screenings program of health care workers. DESIGN: For the pulmonary tuberculosis (TB) screenings program, T-SPOT.TB (one of interferon-gamma release assays: IGRA) were performed on 332 health care workers (HCWs) with normal chest roentgenogram and without the history of TB treatment. Low-dose computed tomography (LDCT) was also performed on IGRA positive HCWs. RESULTS: Ten of 332 subjects were positive IGRA. LDCT was performed on IGRA positive 10 subjects. Abnormal findings were noted in 2 of 10 subjects by LDCT. One had CT findings compatible with active TB and finally diagnosed as active TB. Another had scarring shadow at right S5 and lingular segment. Nine of 10 IGRA positive subjects were judged as latent tuberculosis infection (LTBI). Three hundred twenty-one subjects with negative and borderline IGRA of 332 HCWs were judged as not infected with TB. CONCLUSION: Combined use of IGRA and LDCT for tuberculosis screening program of HCWs was found to be effective for early diagnosis of TB, accurate diagnosis of LTBI and judgment of non-infective subjects.
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Personal de Salud , Ensayos de Liberación de Interferón gamma , Tomografía Computarizada por Rayos X/métodos , Tuberculosis/diagnóstico , Adulto , Femenino , Humanos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional , Masculino , Persona de Mediana Edad , Exposición Profesional , Dosis de RadiaciónAsunto(s)
Adenocarcinoma/complicaciones , Ascitis/etiología , Síndrome de Meigs/diagnóstico , Neoplasias Quísticas, Mucinosas y Serosas/complicaciones , Derrame Pleural/etiología , Neoplasias Uterinas/complicaciones , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ascitis/diagnóstico por imagen , Carboplatino/administración & dosificación , Femenino , Humanos , Histerectomía , Neoplasias Quísticas, Mucinosas y Serosas/diagnóstico , Neoplasias Quísticas, Mucinosas y Serosas/patología , Neoplasias Quísticas, Mucinosas y Serosas/terapia , Epiplón/cirugía , Paclitaxel/administración & dosificación , Derrame Pleural/diagnóstico por imagen , Radiografía Torácica , Salpingooforectomía , Tomografía Computarizada por Rayos X , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapiaRESUMEN
BACKGROUND: Chronic cough is one of the most common symptoms of respiratory diseases and can adversely affect patients' quality of life and interfere with social activities, resulting in a significant social burden. A survey is required to elucidate the frequency and treatment effect of chronic cough. However, clinical studies that cover all of Japan have not yet been conducted. METHODS: Patients who presented with a cough that lasted longer than 8 weeks and visited the respiratory clinics or hospitals affiliated with the Japan Cough Society during the 2-year study period were registered. RESULTS: A total of 379 patients were enrolled, and those who did not meet the definition of chronic cough were excluded. A total of 334 patients were analyzed: 201 patients had a single cause, and 113 patients had two or more causes. The main causative diseases were cough variant asthma in 92 patients, sinobronchial syndrome (SBS) in 36 patients, atopic cough in 31 patients, and gastroesophageal reflux (GER)-associated cough in 10 patients. The time required to treat undiagnosed patients and those with SBS was significantly longer and the treatment success rate for GER-associated cough was considerably poor. CONCLUSIONS: We confirmed that the main causes of chronic cough were cough variant asthma, SBS, atopic cough, and their complications. We also showed that complicated GER-associated cough was more likely to become refractory. This is the first nationwide study in Japan of the causes and treatment effects of chronic cough.
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Asma Variante con Tos , Reflujo Gastroesofágico , Humanos , Tos Crónica , Japón/epidemiología , Prevalencia , Calidad de Vida , Tos/epidemiología , Tos/etiología , Tos/diagnóstico , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/epidemiología , Enfermedad CrónicaRESUMEN
Background: To determine the effectiveness of baricitinib in patients with coronavirus disease 2019 (COVID-19), investigate whether baricitinib prevents the need for invasive mechanical ventilation and identify patient subgroups that would benefit from baricitinib. Methods: This observational matched-cohort study was conducted by the Japan COVID-19 Task Force, a nationwide multicenter consortium. Patients with COVID-19 aged ≥18 years were identified from 70 hospitals in Japan. Among patients with confirmed COVID-19 from February 2020 to September 2021, those receiving baricitinib were propensity-score matched with controls. Results: Among 3309 patients, 144 propensity score-matched pairs were identified. Thirteen (9.0%) patients in the baricitinib group and 27 (18.8%) in the control group required invasive mechanical ventilation during the disease course (odds ratio, 0.43). Although the baricitinib group had more severe disease, there were no significant differences in the intensive care unit admission rates (odds ratio, 1.16) and mortality rates (odds ratio, 0.74) between groups. In subgroup analyses, baricitinib was associated with a significant reduction in the need for invasive mechanical ventilation in patients requiring oxygen support (odds ratio, 0.28), with rapid shadow spread on chest radiography (odds ratio, 0.11), or treated with remdesivir (odds ratio, 0.27), systemic corticosteroids (odds ratio, 0.31), or anticoagulants (odds ratio, 0.17). Conclusions: Baricitinib is effective at preventing the need for invasive mechanical ventilation in patients with COVID-19.
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This study aimed to elucidate the 12-month durability of neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients infected during the 2020 workplace outbreaks of coronavirus disease 2019 (COVID-19) in Japan. We followed 33 Japanese patients infected with SARS-CoV-2 in April 2020 for 12 months (12M). Patients were tested for NAbs and for antibodies against the SARS-CoV-2 nucleocapsid (anti-NC-Ab) and antibodies against the spike receptor-binding domain (anti-RBD-Ab). Tests were performed at 2M, 6M, and 12M after the primary infection (api) with commercially available test kits. In 90.9% (30/33) of patients, NAbs persisted for 12M api, though the median titers significantly declined from 78.7% (interquartile range [IQR]: 73.0-85.0%) at 2M, to 59.8% (IQR: 51.2-77.9) at 6M (P = 0.008), and to 56.2% (IQR: 39.6-74.4) at 12M (P<0.001). An exponential decay model showed that the NAb level reached undetectable concentrations at 35.5 months api (95% confidence interval: 26.5-48.0 months). Additionally, NAb titers were significantly related to anti-RBD-Ab titers (rho = 0.736, P<0.001), but not to anti-NC-Ab titers. In most patients convalescing from COVID-19, NAbs persisted for 12M api. This result suggested that patients need a booster vaccination within one year api, even though NAbs could be detected for over two years api. Anti-RBD-Ab titers could be used as a surrogate marker for predicting residual NAb levels.
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COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Formación de Anticuerpos , COVID-19/epidemiología , Brotes de Enfermedades , Humanos , Japón/epidemiología , Glicoproteína de la Espiga del Coronavirus , Lugar de TrabajoRESUMEN
BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is more effective than cytotoxic chemotherapy in improving overall survival (OS) among patients with advanced-stage non-small cell lung cancer (NSCLC). Recently, chemotherapy combined with ICI has been found to yield good outcomes. However, ICI monotherapy is still considered an important treatment option. Data on long-term progression-free survival (PFS) and OS in real-world settings are limited. PATIENTS AND METHODS: This was a multicenter retrospective observational study. A total of 435 consecutive patients histologically diagnosed with advanced, metastatic, or recurrent NSCLC treated with ICI monotherapy were enrolled in this study from December 2015 to December 2018. Clinical data were collected from electronic medical records and pharmacy databases. RESULTS: The PFS and OS of the patients were 3.4 and 13.0 months, respectively. The objective response and disease control rates were 22.8% and 54.9%, respectively, and the 4-year survival rate was 17.9%. Multivariate analyses revealed that elder patients (>70 years), good Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, programmed death-ligand 1 tumor proportion score (PD-L1 TPS) of ≥ 50%, absence of bone metastasis, and presence of immune-related skin toxicity, which is an immune-related adverse event, were correlated with good PFS. Moreover, good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good OS. CONCLUSIONS: The 4-year survival rate was 17.9%. Good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good PFS and OS.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
PURPOSE: Using CT findings from a prospective, randomized, open-label multicenter trial of favipiravir treatment of COVID-19 patients, the purpose of this study was to compare the utility of machine learning (ML)-based algorithm with that of CT-determined disease severity score and time from disease onset to CT (i.e., time until CT) in this setting. MATERIALS AND METHODS: From March to May 2020, 32 COVID-19 patients underwent initial chest CT before enrollment were evaluated in this study. Eighteen patients were randomized to start favipiravir on day 1 (early treatment group), and 14 patients on day 6 of study participation (late treatment group). In this study, percentages of ground-glass opacity (GGO), reticulation, consolidation, emphysema, honeycomb, and nodular lesion volumes were calculated as quantitative indexes by means of the software, while CT-determined disease severity was also visually scored. Next, univariate and stepwise regression analyses were performed to determine relationships between quantitative indexes and time until CT. Moreover, patient outcomes determined as viral clearance in the first 6 days and duration of fever were compared for those who started therapy within 4, 5, or 6 days as time until CT and those who started later by means of the Kaplan-Meier method followed by Wilcoxon's signed-rank test. RESULTS: % GGO and % consolidation showed significant correlations with time until CT (p < 0.05), and stepwise regression analyses identified both indexes as significant descriptors for time until CT (p < 0.05). When divided all patients between time until CT of 4 days and that of more than 4 days, accuracy of the combined quantitative method (87.5%) was significantly higher than that of the CT disease severity score (62.5%, p = 0.008). CONCLUSION: ML-based CT texture analysis is equally or more useful for predicting time until CT for favipiravir treatment on COVID-19 patients than CT disease severity score.
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COVID-19 , Algoritmos , Amidas , Inteligencia Artificial , COVID-19/diagnóstico por imagen , Humanos , Pulmón/patología , Estudios Prospectivos , Pirazinas , SARS-CoV-2 , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: Although bronchoscopy has an important role in the diagnosis of lung cancer, more invasive procedures, such as CT-guided biopsy or surgery, are needed when transbronchial approaches fail. OBJECTIVE: We investigated the usefulness of endobronchial ultrasonic-transbronchial needle aspiration (EBUS-TBNA) for lung cancer diagnosis. SUBJECTS AND METHODS: We retrospectively evaluated 122 cases who were finally diagnosed to have lung cancer from among 388 cases who underwent bronchoscopy because of abnormal shadows on their chest X-ray or CT. When bronchoscopic approaches were possible, conventional transbronchial lung biopsy or cytology (conventional approaches) were done. EBUS-TBNA was added whenever mediastinal or hilar lymph nodes enlarged to more than 1 cm in diameter, or if there were lesions attached to the lower respiratory tract. The diagnostic accuracy of conventional approaches and EBUS-TBNA were assessed. RESULTS: The number of cases diagnosed as lung cancer by conventional approaches was 79 cases (64.8%) among the 122 cases examined. Of the 43 cases undiagnosed by these procedures, 27 cases were diagnosed as lung cancer by EBUS-TBNA. Thus, 106 cases (86.9%) were diagnosed as lung cancer using conventional approaches plus EBUS-TBNA. No severe complications were observed in all the subjects. CONCLUSION: EBUS-TBNA is a safe and useful approach for the diagnosis of lung cancer together with staging.
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Biopsia con Aguja/métodos , Endosonografía , Neoplasias Pulmonares/patología , Adulto , Anciano , Anciano de 80 o más Años , Bronquios/patología , Broncoscopía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodosRESUMEN
A survey on chemotherapy-induced nausea, vomiting and food intake was conducted on 126 outpatients receiving chemotherapy during a days from February 1 to February 12, 2010 in our hospital. Responses were obtained from 66 outpatients. In the acute phase, 11%of the patients developed nausea. In the late phase, 35%patients developed nausea. The development of nausea was significantly increased in the late phase, compared to the acute phase(p=0. 0008). Though nobody developed vomiting in the acute phase, 3% of the patients developed vomiting in the late phase. For food intake, in the acute phase, nobody showed a"reduced amount of diet", and 12% showed"not eating". In the late phase, 26% of the patients showed"reduced amount of food", and 8%"not eating". Food intake was significantly decreased in the late phase, compared in acute phase(p=0. 0001). Currently, in our hospital, steroids and/or 5-HT3 antagonists are given for antiemetic therapy, but the effect is not enough. We should add other antiemetics, which act in the late phase.
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Antineoplásicos/efectos adversos , Regulación del Apetito/efectos de los fármacos , Náusea/inducido químicamente , Neoplasias/tratamiento farmacológico , Pacientes Ambulatorios , Vómitos/inducido químicamente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Humanos , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
BACKGROUND: PINNACLE-4 evaluated the efficacy and safety of the long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) in patients from Asia, Europe, and the USA with moderate-to-very severe chronic obstructive pulmonary disease (COPD). This pre-specified analysis included Japanese patients in PINNACLE-4. METHODS: In this double-blind randomized study (NCT02343458), patients received GFF MDI (18/9.6 µg), glycopyrrolate (GP) MDI (18 µg), formoterol fumarate (FF) MDI (9.6 µg), or placebo MDI twice daily for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over Weeks 12-24. Secondary lung function endpoints, patient-reported outcomes, and safety were assessed. The Japanese subpopulation (n = 150) analyses were exploratory. RESULTS: GFF MDI improved change from baseline in morning pre-dose trough FEV1 over Weeks 12-24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences [95% confidence interval]: 69 [8-131], 60 [-1 to 121], and 275 [180-370] mL, respectively). GFF MDI numerically improved Transition Dyspnea Index focal score and change from baseline in St George's Respiratory Questionnaire total score versus placebo MDI (LSM differences 0.19 and -3.78, respectively). Treatment-related adverse events occurred in ≤4.5% of patients in any treatment group. CONCLUSIONS: GFF MDI improved lung function versus monocomponents and placebo MDI in the Japan subpopulation of PINNACLE-4. The efficacy and safety results were generally consistent with those of the global study population, supporting the use of GFF MDI in Japanese patients with moderate-to-very severe COPD.
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Sistemas de Liberación de Medicamentos/métodos , Fumarato de Formoterol/administración & dosificación , Glicopirrolato/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Seguridad , Índice de Severidad de la Enfermedad , Suspensiones , Resultado del TratamientoRESUMEN
OBJECTIVES: Immune checkpoint inhibitors (ICIs) have proven to be effective treatment for lung cancer. However, a precise predictive immuno-oncology biomarker is still under development. We investigated the associations among PD-L1 expression, tumor mutational burden (TMB), and oncogenic driver alterations in advanced non-small cell lung cancer (NSCLC) patients treated with ICIs. MATERIALS AND METHODS: This multicenter cohort study included 1017 lung cancer patients. PD-L1 expression using four IHC assays (22C3, 28-8, SP263, SP142), TMB by whole-exome sequencing and oncogenic driver alterations were analyzed comprehensively. Clinical characteristics, treatment and survival data were collected. RESULTS: The results of 22C3 and 28-8 for PD-L1 expression showed acceptable concordance (k = 0.89; 95% confidence interval [CI], 0.87-0.92), and the clinical outcomes of ICIs classified according to PD-L1 expression by both assays were also approximately the same. There was slight concordance (k = 0.16; 95% CI, 0.11-0.22) between 22C3 and SP142, and high PD-L1 expression by SP142 was correspond to very high PD-L1 expressions by other assays. Patients with both high PD-L1 expression and high TMB showed a good response to ICIs with the response rate of 64% and median progression-free survival of 9.0 months despite of small population. Common EGFR or STK11 mutations showed a lower rate of high PD-L1 expression and a worse efficacy of ICIs and KRAS mutations had no negative impact on response to ICIs. CONCLUSION: Comprehensive assessment of PD-L1 expression, TMB, and oncogenic driver alterations would help to better predict the clinical outcomes of ICIs in NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Estudios de Cohortes , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genéticaRESUMEN
Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a generally slow-progressing rare disorder of unknown etiology. The direct cause of death in cases of IPPFE is rarely investigated. We experienced an autopsy case of a Japanese man with IPPFE and found aspiration pneumonia to be the major trigger of death. The individual had left vocal cord paralysis at admission, which may have contributed to aspiration pneumonia, and which probably was affected by the fibrous adhesion of the left apex of the chest wall resulting from IPPFE. The prevention of aspiration pneumonia is important for maintaining the respiratory function, especially in IPPFE patients with repeated pneumothorax.
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Pulmón/patología , Tejido Parenquimatoso/patología , Parálisis de los Pliegues Vocales/complicaciones , Parálisis de los Pliegues Vocales/patología , Anciano , Autopsia , Progresión de la Enfermedad , Fibrosis , Humanos , Masculino , Neumonía por Aspiración/patología , Tomografía Computarizada por Rayos X/métodos , Parálisis de los Pliegues Vocales/diagnósticoRESUMEN
INTRODUCTION: Various stimuli to the dentin surface elicit dentinal pain by inducing dentinal fluid movement causing cellular deformation in odontoblasts. Although odontoblasts detect deformation by the activation of mechanosensitive ionic channels, it is still unclear whether odontoblasts are capable of establishing neurotransmission with myelinated A delta (Aδ) neurons. Additionally, it is still unclear whether these neurons evoke action potentials by neurotransmitters from odontoblasts to mediate sensory transduction in dentin. Thus, we investigated evoked inward currents and evoked action potentials form trigeminal ganglion (TG) neurons after odontoblast mechanical stimulation. METHODS: We used patch clamp recordings to identify electrophysiological properties and record evoked responses in TG neurons. RESULTS: We classified TG cells into small-sized and medium-sized neurons. In both types of neurons, we observed voltage-dependent inward currents. The currents from medium-sized neurons showed fast inactivation kinetics. When mechanical stimuli were applied to odontoblasts, evoked inward currents were recorded from medium-sized neurons. Antagonists for the ionotropic adenosine triphosphate receptor (P2X3), transient receptor potential channel subfamilies, and Piezo1 channel significantly inhibited these inward currents. Mechanical stimulation to odontoblasts also generated action potentials in the isolectin B4-negative medium-sized neurons. Action potentials in these isolectin B4-negative medium-sized neurons showed a short duration. Overall, electrophysiological properties of neurons indicate that the TG neurons with recorded evoked responses after odontoblast mechanical stimulation were myelinated Aδ neurons. CONCLUSIONS: Odontoblasts established neurotransmission with myelinated Aδ neurons via P2X3 receptor activation. The results also indicated that mechanosensitive TRP/Piezo1 channels were functionally expressed in odontoblasts. The activation of P2X3 receptors induced an action potential in the Aδ neurons, underlying a sensory generation mechanism of dentinal pain.
Asunto(s)
Potenciales de Acción/fisiología , Mecanorreceptores/fisiología , Odontoblastos/fisiología , Canales de Potencial de Receptor Transitorio/fisiología , Ganglio del Trigémino/citología , Animales , Técnicas de Cocultivo/métodos , Femenino , Masculino , Proteínas de la Membrana/fisiología , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Ganglio del Trigémino/fisiologíaRESUMEN
Odontoblasts play a crucial role in dentin formation and sensory transduction following the application of stimuli to the dentin surface. Various exogenous and endogenous stimuli elicit an increase in the intracellular free calcium concentration ([Ca2+]i) in odontoblasts, which is mediated by Ca2+ release from intracellular Ca2+ stores and/or Ca2+ influx from the extracellular medium. In a previous study, we demonstrated that the depletion of Ca2+ stores in odontoblasts activated store-operated Ca2+ entry (SOCE), a Ca2+ influx pathway. However, the precise biophysical and pharmacological properties of SOCE in odontoblasts have remained unclear. In the present study, we examined the functional expression and pharmacological properties of Ca2+ release-activated Ca2+ (CRAC) channels that mediate SOCE and evaluated the alkali sensitivity of SOCE in rat odontoblasts. In the absence of extracellular Ca2+, treatment with thapsigargin (TG), a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, induced an increase in [Ca2+]i. After [Ca2+]i returned to near-resting levels, the subsequent application of 2.5 mM extracellular Ca2+ resulted in an increase in [Ca2+]i which is a typical of SOCE activation. Additionally, application of 2-methylthioadenosine diphosphate trisodium salt (2-MeSADP), a P2Y1,12,13 receptor agonist, or carbachol (CCh), a muscarinic cholinergic receptor agonist, in the absence of extracellular Ca2+, induced a transient increase in [Ca2+]i. The subsequent addition of extracellular Ca2+ resulted in significantly higher [Ca2+]i in 2-MeSADP- or CCh-treated odontoblasts than in untreated cells. SOCE, that is activated by addition of extracellular Ca2+ in the TG pretreated odontoblasts was then suppressed by Synta66, BTP2, or lanthanum, which are CRAC channel inhibitors. Treatment with an alkaline solution enhanced SOCE, while treatment with HC030031, a TRPA1 channel antagonist, inhibited it. The amplitude of SOCE at pH 9 in the presence of HC030031 was higher than that at pH 7.4 in the absence of HC030031. These findings indicate that CRAC channel-mediated alkali-sensitive SOCE occurs in odontoblasts. SOCE is mediated by P2Y and muscarinic-cholinergic receptors, which are activated by endogenous ligands in odontoblasts.
RESUMEN
BACKGROUND: COPD is a major global cause of mortality and morbidity. PINNACLE-4 evaluated the efficacy and safety of GFF MDI (glycopyrrolate/formoterol fumarate metered dose inhaler) in patients from Asia, Europe, and the USA with moderate-to-very severe COPD. METHODS: In this double-blind, placebo-controlled, Phase III study, patients were randomized to treatment with GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI (all twice daily) for 24 weeks. Lung function, patient-reported outcomes (symptoms and health-related quality of life), and safety were assessed. RESULTS: Of the 1,756 patients randomized, 1,740 patients were included in the intent-to-treat population (mean age 64.2 years, 74.1% male, and 40.2% Asian). GFF MDI significantly improved morning predose trough FEV1 at Week 24 (primary endpoint) vs placebo MDI, GP MDI, and FF MDI (least squares mean differences: 165, 59, and 72 mL, respectively; all P<0.0001). GFF MDI also significantly improved other lung function endpoints vs placebo MDI, GP MDI, and FF MDI and patient-reported outcomes vs placebo MDI and GP MDI. A larger proportion of patients treated with GFF MDI achieved the minimum clinically important difference in Transition Dyspnea Index score vs GP MDI and placebo MDI and in St George's Respiratory Questionnaire score vs placebo MDI. Adverse event rates were similar across treatment groups. CONCLUSION: These results demonstrated the efficacy of GFF MDI in patients with moderate-to-very severe COPD. GFF MDI was well tolerated, with a safety profile commensurate with long-acting bronchodilators.