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BACKGROUND: Several patients treated with osimertinib experience progressive disease. The aim was to clarify the mechanisms underlying resistance to osimertinib. METHODS: ELUCIDATOR: A multi-centre, prospective, observational study involved chemotherapy-naive patients with advanced non-small cell lung cancer receiving osimertinib. Mutations in cancer-associated genes, detected via ultrasensitive next-generation sequencing of circulating tumour deoxyribonucleic acid samples, were collected at baseline and after progressive disease detection. These paired plasma samples were compared. RESULTS: Of 188 patients enrolled (May 2019-January 2021), 178 (119 females [67 %]) median age 74 years, were included. Patients, n = 95 (53 %) had epidermal growth factor receptor exon 19 deletion mutations. Among 115 patients with progressive disease, circulating tumour deoxyribonucleic acid levels of 85 patients were analysed. MET amplification (n = 4), TP53 mutations (n = 4), PIK3CA mutations (n = 3), BRINP3 mutation (n = 2), BRAF mutation (n = 2), APC mutation (n = 1), RET mutation (n = 1) and epidermal growth factor receptor (EGFR) resistance mutation, and C797S (n = 1) were detected. Patients with baseline TP53 mutations, with MET or EGFR amplification had shorter progression-free (PFS) and overall survival. Patients with PIK3CA mutations tended to shorter PFS. CONCLUSION: MET amplification and PIK3CA mutation mechanisms underly resistance to osimertinib in patients. Patients with coexisting mutations or amplifications at baseline had shorter PFS and overall survival.
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BACKGROUND/AIM: For patients treated with osimertinib as first-line therapy, there have been no studies comparing both progression-free survival (PFS) and overall survival (OS) according to performance status (PS). Furthermore, no studies have examined differences in baseline genetic abnormalities between patients with poor and good PS. Therefore, we aimed to investigate differences in baseline genetic abnormalities and treatment effects between patients with poor and good PS who received osimertinib as the primary treatment. PATIENTS AND METHODS: This is a secondary analysis of the ELUCIDATOR study, which is a multi-center prospective observational study in Japan that assessed mechanisms underlying resistance to osimertinib as first-line treatment for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. RESULTS: There were 153 and 25 patients in the good and poor PS groups, respectively. Multivariate analysis revealed no significant between-group differences in PFS (hazards ratio [HR]: 0.98, 95% confidence interval [CI]: 0.52-1.72, p = 0.946). Multivariate analysis of OS revealed that poor PS was a poor prognostic factor (HR: 2.67, 95% CI: 1.43-4.73, p = 0.003). Regarding baseline genetic abnormalities, there was a significant increase in APC-positive cases (20.0% vs. 2.2%, p = 0.009) and a trend toward more CTNNB1-positive cases in the poor PS group than in the good PS group (14.3% vs. 2.9%, p = 0.062). CONCLUSION: There was no between-group difference in PFS, although OS was significantly inferior in the poor PS group. Additionally, there was a significant increase in APC-positive cases and a trend toward more CTNNB1-positive cases in the poor PS group.
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Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Acrilamidas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Femenino , Anciano , Receptores ErbB/genética , Persona de Mediana Edad , Compuestos de Anilina/uso terapéutico , Estudios Prospectivos , Antineoplásicos/uso terapéutico , Japón , Supervivencia sin Progresión , Anciano de 80 o más Años , Adulto , beta Catenina/genética , Indoles , PirimidinasRESUMEN
BACKGROUND: This study evaluated the efficacy and safety of the combination chemotherapy of docetaxel plus S-1 in patients with previously treated non-small cell lung cancer (NSCLC) compared to docetaxel alone. METHODS: Patients with previously treated NSCLC were randomly assigned to docetaxel alone (arm A) or a combination of docetaxel and S-1 (arm B) for a maximum of four cycles. The primary endpoint was overall survival (OS). RESULTS: The study was terminated early because of poor accrual. The number of patients evaluated were 74 and 77 in arm A and arm B, respectively. The median OS was 9.8 months (95% confidence interval [CI]: 6.8-15.2) and 12.3 months (95% CI: 9.2-14.5) in arms A and B, respectively. In arms A and B, the median progression-free survival was 3.5 months (95% CI: 2.7-4.0) and 4.1 months (95% CI: 3.2-4.7), respectively. No statistically significant difference was observed in OS (hazard ratio [HR]: 0.984, 95% CI: 0.682-1.419, p = 0.4569) or progression-free survival (HR: 0.823, 95% CI: 0.528-1.282, p = 0.0953). The major toxicity was myelosuppression. The incidence of grade 3 or more neutropenia was higher in arm A than in arm B (44.6% vs. 35.1%). However, the incidence of grade 3 or more febrile neutropenia and infection with neutropenia (12.2% vs. 22.1%) was more frequently observed in arm B. CONCLUSIONS: The prematurely terminated study did not show the benefit of two cytotoxic agents over single-agent therapy for previously treated NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neutropenia , Humanos , Docetaxel/uso terapéutico , Taxoides/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Previous trials suggest that older adults with non-small cell lung cancer (NSCLC) derive benefit from platinum doublet combination therapy, but its superiority is controversial. Although geriatric assessment variables are used to assess the individual risk of severe toxicity and clinical outcomes in older patients, the standard first-line treatment is still debated. Therefore, we aimed to identify the risk factors for clinical outcomes in older patients with NSCLC. METHODS: Patients aged ≥75 years with advanced NSCLC treated at any of 24 National Hospital Organization institutions completed a pre-first-line chemotherapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. We evaluated whether these variables were the risk factors for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 148 patients with advanced NSCLC were treated with combination therapy (n = 90) or monotherapy (n = 58). Median PFS was 5.3 months and OS was 13.6 months. We identified that hypoalbuminemia (hazard ratio [HR] 2.570, 95% confidence interval [CI]: 1.117-5.913, p = 0.0264) was a risk factor for PFS and monotherapy (HR 1.590, 95% CI: 1.070-2.361, p = 0.0217), lactate dehydrogenase (HR 3.682, 95% CI: 1.013-13.39, p = 0.0478), and high C-reactive protein (HR 2.038, 95% CI: 1.141-3.642, p = 0.0161) were risk factors for OS. The median OS was significantly longer in patients treated with combination therapy than in those who received monotherapy (16.5 months vs. 10.3 months; HR 0.684, 95% CI: 0.470-0.995, p = 0.0453). DISCUSSION: Platinum doublet combination therapy may be beneficial in older patients with NSCLC. Identification of risk factors will assist in the development of a personalized treatment strategy.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Anciano , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Antineoplásicos/uso terapéutico , Japón , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , HospitalesRESUMEN
Introduction: Pembrolizumab became available in Japan in February 2017 for first-line monotherapy of unresectable advanced and metastatic NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. This retrospective chart review study aimed to describe real-world clinical outcomes of first-line pembrolizumab monotherapy, including for patients 75 years or older, who are under-represented in clinical trials. Methods: We identified patients (≥20 y old) at 23 sites initiating first-line pembrolizumab monotherapy from July 1, 2017, to December 20, 2018, for stages IIIB, IIIC, and IV NSCLC with PD-L1 TPS greater than or equal to 50% and Eastern Cooperative Oncology Group performance status of 0 to 2 or unknown. Patients with actionable genomic alterations (EGFR, ALK, ROS1, BRAF) and clinical trial participants were excluded. Time-to-event outcomes were estimated using Kaplan-Meier, with data cutoff on September 30, 2019. Results: Of 441 eligible patients (78% men), 303 (69%) were younger than 75 years and 138 (31%) were 75 years or older; median age was 70 years. With median follow-up of 13.5 months, median overall survival (OS) was not reached (NR); 12- and 24-month OS rates were 72% and 58%, respectively. For ages younger than 75 and 75 years or older, median OS was NR and 23.5 months (95% confidence interval: 16.2-NR), respectively; 12-month OS rates were 74% and 67% and 24-month OS rates were 62% and 48%, respectively. Median real-world progression-free survival was similar in the two age groups (10.1 and 9.5 mo, respectively), as was median real-world time on treatment with pembrolizumab (5.7 and 5.6 mo). Conclusions: These findings complement clinical trial results, adding real-world evidence supporting benefits of first-line pembrolizumab monotherapy for advanced NSCLC with PD-L1 TPS greater than or equal to 50%, including for patients 75 years or older.
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INTRODUCTION: Previous studies have developed risk stratification schemas to assess systemic therapy toxicity. However, it is controversial which geriatric assessment variables should be used to assess the individual risk of severe treatment-associated toxicity in older adult patients. MATERIALS AND METHODS: Patients aged ≥70 years with advanced non-small cell lung cancer (NSCLC) treated at 24 National Hospital Organization institutions completed a pre-first-line systemic therapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. Patients were followed through one cycle of systemic therapy to assess grade 3 (severe) to grade 5 (death) adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: In total, 348 advanced NSCLC patients with a median age of 76 years (range, 70 to 95 years) joined this prospective study. Severe adverse events ≥grade 3 occurred in 136 patients (39.1%). Predictors of hematologic toxicity were treatment variables, body mass index, body weight loss, and limitation in daily living due to dementia. These predictors provided the predictive model of hematologic toxicity ≥grade 3; 0 point (22.2%), 1 point (33.8%), 2 points (59.6%), ≥3 points (73.3%). Sex, daily living independence level, and lactate dehydrogenase levels were associated with non-hematologic toxicity ≥grade 3 in multivariate analysis. A scoring system using these predictors distinguished the risk levels of non-hematologic toxicity ≥grade 3; 0 point (6.6%), 1 point (12.2%), 2 points (39.0%), 3 points (75.0%). DISCUSSION: A stratification using individual extracted risk factors may be useful to predict the vulnerability to systemic therapy in older adult NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Humanos , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Estudios Prospectivos , Neoplasias Pulmonares/tratamiento farmacológico , Japón , HospitalesRESUMEN
The number of cases with Mycobacterium avium and Mycobacterium intracellulare lung diseases (Mycobacterium avium complex lung disease [MACLD]) are increasing globally. Lung cancer can sometimes present as a comorbidity with MACLD; however, the clinical presentation and outcomes of comorbid MACLD following lung cancer resection remain unclear. Therefore, we retrospectively assessed 17 patients with MACLD undergoing lung cancer resection to determine the impact of lung cancer surgery on comorbid MACLD. Of the 17 patients, Mycobacterium avium and Mycobacterium intracellulare were present in 15 and 2 patients, respectively; 14 patients had stage I lung cancer and underwent lobectomy. Ten patients were postoperatively observed for MACLD without any further intervention, five patients underwent additional resection for conspicuous MACLD lesions, and the remaining two patients underwent complete resection for MACLD and lung cancer within the same lobe followed by rifampicin, ethambutol, and clarithromycin (RECAM) therapy. Seven patients exhibited postoperative MACLD exacerbation, six of whom developed exacerbation in the operated ipsilateral residual lobes. Six of these seven patients received RECAM, three of whom (43%) subsequently exhibited improvement. Attention should be paid to MACLD exacerbation during postoperative follow-up, especially in ipsilateral lobes. Although RECAM therapy may be beneficial in alleviating MACLD exacerbation, further investigation is warranted to validate these results.
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BACKGROUND: Gefitinib (G) is a recommended molecular-targeted agent for elderly patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Docetaxel (Doc) and pemetrexed (Pem) have similar efficacies, and either is often used as the sole agent during treatment. The efficacy of continuing G after progressive disease (PD) develops has been reported. It remains unclear whether the continuation of G in combination with a single cytotoxic agent beyond PD is beneficial for elderly patients. Here, we conducted a randomized phase II study to assess the efficacy and safety of cytotoxic chemotherapy with G for elderly patients with progressive EGFR-mutant NSCLC. METHODS: Elderly patients with EGFR-mutant NSCLC with PD previously treated with G were enrolled. Patients received Pem 500 mg/m or Doc 60 mg/m every 21 days and were randomly assigned to receive chemotherapy with 250 mg G (G+ Doc/Pem arm) or without G (Doc/Pem arm) until further disease progression or unacceptable toxicity. RESULTS: This trial was terminated early owing to slow accrual. A group of 22 patients underwent analysis. The primary endpoint, progression-free survival (PFS), was significantly longer in the G + Doc/Pem arm (median: 1.6 months vs. 5.6 months, hazard ratio = 0.40, 95% CI: 0.16-0.99, p = 0.0391). Adverse events ≥ grade 3 were more frequent in the G + Doc/Pem arm (45.5% vs. 90.9%, p = 0.032). CONCLUSIONS: Patients on G and Pem or Doc beyond PD showed a longer PFS than those on single-agent chemotherapy; however, it was associated with increased toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Progresión de la Enfermedad , Docetaxel/uso terapéutico , Receptores ErbB/genética , Gefitinib/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Pemetrexed/uso terapéuticoRESUMEN
BACKGROUND: Aspergillus spp. is identified morphologically without antifungal susceptibility tests (ASTs) in most clinical laboratories. The aim of this study was to examine the clinical impact of the morphological identification of Aspergillus spp. to ensure the adequate clinical management of Aspergillus infections. PATIENTS/METHODS: Aspergillus isolates (n = 126) from distinct antifungal treatment-naïve patients with aspergillosis were first identified morphologically, followed by species-level identification via DNA sequencing. An AST for itraconazole (ITC) and voriconazole (VRC) was performed on each Aspergillus isolate. RESULTS: Based on the genetic test results, morphology-based identification was accurate for >95% of the isolates at the species sensu lato level although the test concordance of Aspergillus spp. with low detection rates was low. The rates of cryptic species were found to be 1.2% among the isolates of A. fumigatus complex and 96.8% in the A. niger complex. Cryptic species with lower susceptibilities to antifungal drugs than sensu stricto species among the same Aspergillus section were as follows: The A. lentulus (n = 1) isolates had low susceptibilities to azoles among the A. fumigatus complex species (n = 86), and A. tubingensis isolates (n = 18) exhibited lower susceptibility to azoles among the A. niger complex species (n = 31). CONCLUSION: Diagnostic accuracy was high at the A. fumigatus and A. niger complex level. However, in the presence of cryptic species, a solely morphological identification was insufficient. Particularly, ITC and VRC might be inappropriate for aspergillosis treatment when the A. niger complex is identified morphologically because it is possible that the Aspergillus isolate is A. tubingensis.
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Antifúngicos , Aspergilosis , Aspergillus/clasificación , Antifúngicos/farmacología , Aspergilosis/diagnóstico , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Aspergillus/efectos de los fármacos , Humanos , Itraconazol/farmacología , Pruebas de Sensibilidad Microbiana , Voriconazol/farmacologíaRESUMEN
This study aimed to clarify the characteristics of patients with lung cancer undergoing treatment until the onset of tuberculosis. Between 2005 and 2019, patients who were admitted to Tokyo National Hospital due to tuberculosis during lung cancer treatment were examined retrospectively. There were 42 patients, and detailed medical information was obtained in 39 patients. The median age of the 39 patients were 75 years (range: 47-92 years), of which 33 were males and 36 were Japanese Baby Boomers or older. Regarding risk factors for developing tuberculosis, smoking was noted in 34 cases, oral corticosteroid use in 13, and previous tuberculosis in six. Thirty-seven patients had one risk factor and 19 had two or more risk factors, but diagnosis of latent tuberculosis infection (LTBI) was obtained in only one patients, and none had received LTBI treatment. The first-line treatment for lung cancer was resection in 13 cases, chemoradiotherapy in 6, chemotherapy in 10, radiation therapy in 3, laser therapy in 1, and best supportive care (BSC) alone in 6. At tuberculosis onset, BSC accounted for 17 cases, but other situations were considerably existed such as anticancer medication (12 cases), and observation after lung cancer treatment (10 cases). Tuberculosis occurred in various situations in elderly patients with lung cancer. It is critical to actively evaluate the risk of tuberculosis and consider LTBI screening and treatment.
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Tuberculosis Latente , Neoplasias Pulmonares , Tuberculosis , Anciano , Anciano de 80 o más Años , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/epidemiología , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Estudios Retrospectivos , Tuberculosis/diagnóstico , Tuberculosis/epidemiologíaRESUMEN
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line treatment for patients with nonsmall-cell lung cancer harboring EGFR mutations. We report a 65-year-old Japanese woman with nonsmall-cell lung cancer taking an EGFR-TKI who visited the emergency department with acute nausea and vomiting. Imaging studies demonstrated an incarcerated diaphragmatic hernia. Urgent diagnostic surgery revealed a gap in the diaphragm acting as a hernial orifice, where a metastatic tumor was detected. We consider that regression of the diaphragmatic metastasis by EGFR-TKI therapy resulted in perforation of the diaphragm, causing the diaphragmatic hernia. Gastrointestinal adverse events, e.g. nausea, vomiting and diarrhea, are common during EGFR-TKI treatment. However, this case suggests that in patients with diaphragmatic metastasis, we should consider the rare possibility of diaphragmatic perforation and a subsequent hernia.
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BACKGROUND: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited. METHODS: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group. RESULTS: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001). CONCLUSION: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.
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Quinasa de Linfoma Anaplásico/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/administración & dosificación , Reordenamiento Génico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carbazoles , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Crizotinib/efectos adversos , Femenino , Humanos , Japón , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Piperidinas , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios Retrospectivos , Factores de TiempoRESUMEN
The prevalence of azole-resistant Aspergillus fumigatus (ARAF) among chronic pulmonary aspergillosis (CPA) patients treated with azoles in Japan is unknown. The aim of this study was to determine the detection rate of ARAF in isolates from CPA patients who were treated with azoles for varying durations. The potential mechanism of acquiring resistance was examined by sequencing cyp51A and hmg1, two genes associated with ARAF. A. fumigatus isolates (n = 120) were collected from CPA patients (n = 104) between February 2012 and February 2019, at National Hospital Organization Tokyo National Hospital. The isolates were tested for susceptibility to the azole drugs itraconazole (ITCZ) and voriconazole (VRCZ). The detection rate of ARAF among all isolates was 8.3% (n = 10). Of the 10 resistant isolates, eight were ITCZ-resistant and five were VRCZ-resistant. Among 47 isolates obtained from 36 CPA patients who were treated with ITCZ (for an average of 256 days) and/or VRCZ (for an average of 29 days), the resistance rates were 17.0% and 10.6%, respectively. In addition, 46.2% of 13 isolates obtained from CPA patients with ongoing azole treatment at the time of antifungal therapy failure were resistant to azoles. Among the 10 ARAF isolates, a point mutation was detected in cyp51A in seven isolates and in hmg1 in two isolates. ARAF was detected at a high rate in CPA patients, particularly in those with ongoing long-term azole treatment, at the time of azole antifungal therapy failure.
Aspergillus fumigatus can acquire azole resistance during long-term treatment with azole drugs in patients with chronic pulmonary aspergillosis (CPA). The aim of this study was to determine the detection rate of azole-resistant A. fumigatus (ARAF) in isolates from CPA patients who had been treated with azoles. In addition, a potential mechanism of acquiring resistance was examined by sequencing cyp51A and hmg1, two genes associated with ARAF. A. fumigatus isolates (n = 120) were collected from CPA patients (n = 104). The isolates were tested for susceptibility to the azole drugs itraconazole (ITCZ) and voriconazole (VRCZ). The detection rate of ARAF from all isolates was 8.3% (n = 10). Greater than 10% of the 47 isolates obtained from 36 CPA patients who had been treated with azoles exhibited resistance. Furthermore, 46.2% of 13 isolates obtained from CPA patients with ongoing azole treatment at the time of antifungal therapy failure were resistant to azoles. Among the 10 ARAF isolates, a point mutation was detected in cyp51A in seven isolates and in hmg1 in two isolates. ARAF was detected at a high rate in CPA patients undergoing long-term azole treatment at the time of antifungal therapy failure.
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Antifúngicos/farmacología , Aspergillus fumigatus/efectos de los fármacos , Azoles/farmacología , Azoles/uso terapéutico , Farmacorresistencia Fúngica/genética , Hospitales/estadística & datos numéricos , Aspergilosis Pulmonar/tratamiento farmacológico , Anciano , Aspergillus fumigatus/genética , Azoles/clasificación , Enfermedad Crónica/terapia , Femenino , Proteínas Fúngicas/genética , Genotipo , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Prevalencia , Aspergilosis Pulmonar/epidemiología , Aspergilosis Pulmonar/microbiología , Estudios Retrospectivos , Tokio/epidemiologíaRESUMEN
INTRODUCTION: The new-generation QuantiFERON (QFT)-TB Gold Plus (QFT-Plus) is expected to be useful because it includes a new peptide that is supposed to induce a CD8+ T cell response. There is a need for a new marker with sensitivity higher than that of the conventional IFN-γ release assays owing to false-negative results in the latter. This study aimed to compare cytokines in QFT-plus and QuantiFERON-Gold In-Tube (QFT-GIT) supernatants to discriminate between active tuberculosis and latent tuberculosis infection (LTBI). METHODS: A cross-sectional study was conducted at Tokyo National Hospital, wherein 21 LTBI patients and age and sex-matched active TB patients were randomly selected. The levels of various cytokines were measured and compared using the MAGPIX System, and receiver operating characteristic (ROC) curves were generated. RESULTS: IL-1RA, IFN-γ, CXCL10/IP-10, and CCL4/MIP-1ß levels were higher in the active TB group than in the LTBI group in QFT-GIT antigen (GIT Ag) tubes. In QFT-plus tubes, IL-1RA was higher in TB1 and TB2 tubes, while CCL2/MCP-1 was higher only in TB2 tubes. In Nil tubes, CCL5/RANTES, TNF-α, PDGF-BB, and IL-2 levels were significantly higher in the active TB group. IL-1RA in GIT Ag tubes showed the highest area under the curve of 0.8367. The sensitivity and specificity of IL-1RA were 66.7% (95% confidence interval [CI]: 43.0-85.4) and 90.5% (95% CI: 69.6-98.8), respectively, which were the highest among the cytokines. CONCLUSIONS: IL-1RA level in the QFT-GIT supernatant can be a good marker for discriminating active TB from LTBI.
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Infección Latente , Tuberculosis Latente , Tuberculosis , Estudios Transversales , Humanos , Ensayos de Liberación de Interferón gamma , Proteína Antagonista del Receptor de Interleucina 1 , Tuberculosis Latente/diagnóstico , Tokio , Tuberculosis/diagnósticoRESUMEN
Molecular-targeted drugs (MTDs), such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase inhibitors, are used to treat non-small-cell lung cancer (NSCLC). The incidence of rash caused by EGFR-TKIs and discontinuation of MTDs because of rash are issues. Rapid desensitization therapy (RDT) was performed in five patients who developed severe rash after introduction of MTDs and was successful in four, all of whom showed no rash relapse. RDT may thus be useful for treating rash in patients receiving MTDs for NSCLC.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Exantema , Neoplasias Pulmonares , Preparaciones Farmacéuticas , Quinasa de Linfoma Anaplásico , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Exantema/inducido químicamente , Exantema/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Recurrencia Local de Neoplasia , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
OBJECTIVES: This study evaluated the efficacy of the following interferon (IFN)-γ release assays (IGRAs): QuantiFERON-TB Gold Plus (QFT-Plus), QFT-Gold In-Tube (QFT-GIT), and T-SPOT. TB (T-SPOT) with the quantitative values of IFN-γ response. METHODS: Blood samples were collected from patients with active tuberculosis (TB), latent TB infection (LTBI), individuals with previous TB infection, and healthy volunteers enrolled between May 2017 and June 2018. RESULTS: IGRAs results were analyzed in 175 subjects (76 had active TB, 14 had LTBI, 35 had prior TB infection, and 50 were healthy). QFT-Plus and QFT-GIT revealed equal efficacy for IFN-γ values, and the IFN-γ response in QFTs tended to increase with the spot counts in T-SPOT, with similar high sensitivities (approximately 90%) in the active TB group. The test concordance of two of three IGRAs was optimal among all subjects (κ coefficients: 0.82-0.96). Additionally, the median quantitative values of IFN-γ with QFT-Plus and QFT-GIT were higher in the active TB group than in the LTBI and previous TB groups. CONCLUSION: Three IGRAs showed equivalent efficacy with high sensitivities and higher IFN-γ response in active TB group than that in non-active TB group.
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Infección Latente , Tuberculosis Latente , Tuberculosis , Antivirales , Humanos , Interferón gamma , Ensayos de Liberación de Interferón gamma , Tuberculosis Latente/diagnóstico , Prueba de Tuberculina , Tuberculosis/diagnósticoRESUMEN
OBJECTIVES: A recently released new QuantiFERON (QFT) product, QFT TB Gold plus (QFT-plus), is optimized for both CD4 and CD8 responses and reported to have higher sensitivity compared to the former QFT-3â¯G. Previously, using supernatants of QFT-3â¯G, we and others have demonstrated that cytokines other than IFN-γ may be useful in diagnosing tuberculosis. The present study aimed to identify cytokines that are useful for accurately diagnosing active tuberculosis by using QFT-plus and compared the data to those with QFT-3â¯G. METHODS: Eighty-three active tuberculosis patients and 70 healthy control subjects who were examined by QFT at Tokyo National Hospital from June 2017 to July 2018 were enrolled. QFT-3â¯G and QFT-plus were performed according to the manufacturer's instructions. At the same time, blood cell culture supernatants were collected and assayed for their cytokine levels using R&D Systems Luminex Assay and MAGPIX System. The levels of cytokines were compared between different antigen-containing tubes (3â¯G Ag, TB1 and TB2 tubes), as well as between the patients and the control subjects. ROC curves were drawn, and the AUCs were calculated. RESULTS: Five cytokines, i.e., IL-2, IL-6, IL-8, IP-10 and MIP-1ß, produced by human blood cells in three independent tubes containing different tuberculosis antigens were higher in the 3â¯G Ag tube compared to both the TB1 and TB2 tubes. Further, when the TB1 and TB2 tubes were compared, TB2 showed greater production of only PDGF-BB, and less production of IL-6 and TNF-α. For diagnosing active tuberculosis, the levels of IP-10 were superior to the level of IFN-γ based on showing a larger AUC for ROC curves in our present study setting. Finally, the levels of IFN-γ, IL-1RA, IL-2, IP-10, MCP-1 and MIP-1ß were distinctly different between the active tuberculosis patients and healthy controls. CONCLUSIONS: In summary, there was no cytokine that was higher in the tubes of QFT-plus compared to the tube of QFT-3â¯G, suggesting inferiority of QFT-plus antigens to 3â¯G Ag in terms of elicitation of cytokine production. Our results also suggest the usefulness of cytokines that showed a significant difference between the active tuberculosis patients and the healthy controls-namely, IFN-γ, IL-1RA, IL-2, IP-10, MCP-1 and MIP-1ß-for diagnosing tuberculosis, but the roles of these cytokines in the pathogenesis of tuberculosis need to be elucidated (UMIN000035253).
Asunto(s)
Tuberculosis Latente , Mycobacterium tuberculosis , Tuberculosis , Citocinas , Humanos , Ensayos de Liberación de Interferón gamma , Tuberculosis/diagnósticoRESUMEN
A 77-year-old man with anemia who had undergone 2 abdominal surgeries for colon and gastric cancer experienced dyspnea after swallowing a patency capsule before endoscopy for investigating the cause of anemia. Chest radiography and computed tomography revealed that the patency capsule was located within the bronchus intermedius. It was successfully removed by flexible bronchoscopy. The balloon was placed over the capsule and inflated. Subsequently, the catheter was pulled, while thus dragging the capsule with it and preventing its destruction. In cases of patency capsule aspiration, the capsule must be removed without deformity, before it causes inflammation by releasing barium into the airway.
Asunto(s)
Bronquios/cirugía , Broncoscopía/métodos , Endoscopía Capsular/efectos adversos , Cuerpos Extraños/cirugía , Aspiración Respiratoria/cirugía , Anciano , Humanos , Masculino , Tomografía Computarizada por Rayos XAsunto(s)
Antifúngicos/farmacología , Aspergillus/clasificación , Aspergillus/efectos de los fármacos , Farmacorresistencia Fúngica , Sistema Respiratorio/microbiología , Anciano , Anciano de 80 o más Años , Aspergillus/aislamiento & purificación , Enfermedad Crónica , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Aspergilosis Pulmonar/diagnóstico , Aspergilosis Pulmonar/microbiología , Estudios Retrospectivos , TokioRESUMEN
Active tuberculosis is an important complication in Japanese lung cancer patients. We studied the generation-wise trend of latent tuberculosis infection (LTBI) among lung cancer patients. We analyzed background data including birth year, lung cancer status, and interferon-gamma release assay (IGRA) data of lung cancer patients who were admitted to National Hospital Organization Tokyo National Hospital from 2010 to 2016. Of the 1450 cases, 7 showed active tuberculosis and 45 had previous tuberculosis. Of the remaining 1398 patients, 795 underwent IGRAs and 120 (15%) of them were found to have LTBI. Patients with LTBI were older (p = 0.0005), and the proportion of smokers was also higher in this group (p = 0.0159) than among those without LTBI. LTBI incidence decreased from 33% among patients born in the 1920s to 21%, 15%, 9.8%, and 5.1% among those born in the 1930s, 1940s, 1950s, and after 1960, respectively. A significant decrease in the smoking adjusted risk ratio was also observed with every generation (p < 0.0001). Our study suggests that the total number of patients with active tuberculosis comorbid with lung cancer will greatly decrease in the future in Japan. However, owing to recent improvements in lung cancer prognosis due to advances in cancer medication, careful monitoring for active tuberculosis development may be required in lung cancer patients with LTBI.