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Objective The index of microvascular resistance (IMR) is an invasive method for quantifying the coronary microvasculature independent of the presence and degree of epicardial stenosis during cardiac catheterization, whereas the Selvester QRS score, which is related to myocardial damage, is a relatively simple and non-invasive measurement procedure. We investigated the relationship between the QRS score and coronary microvascular dysfunction (CMD) assessed via IMR. Methods Data from 74 patients who underwent invasive coronary physiological measurements were retrospectively reviewed. Using a coronary wire, we measured IMR by the hyperemic mean transit time and distal coronary pressure. We also determined a simplified QRS score following the Selvester QRS score criteria by 12-lead electrocardiography. After determining the best cutoff value for the QRS score to predict IMR ≥25, which was defined as CMD by the Coronary Vasomotion Disorders International Study Group, patients were categorized into the QRS score ≥3 (n=16) and the QRS score 0-2 (n=58) groups. Results IMR in the QRS score ≥3 group was significantly higher in comparison to the QRS score 0-2 group (31; IQR: 19-57 vs. 20; IQR: 14-29, p<0.01). The percentage of patients with IMR ≥25 in the QRS score ≥3 group was significantly higher than that in the QRS score 0-2 group (69% vs. 34%, p=0.01). Conclusion A higher QRS score was associated with CMD, as estimated by IMR. The Selvester QRS score is noninvasive parameter that is potentially useful for predicting CMD.
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Isquemia Miocárdica , Humanos , Microcirculación/fisiología , Estudios Retrospectivos , Miocardio , Corazón , Resistencia Vascular , Valor Predictivo de las PruebasRESUMEN
Trans-catheter aortic valve replacement (TAVR) is an excellent alternative intervention for surgical aortic valve replacement. Cardiac sympathetic nervous (CSN) function and left atrial (LA) volume are both important prognostic factors in patients with aortic stenosis (AS) after TAVR. The relationship between the two clinical factors is unknown, however. This retrospective observational study aimed to assess the correlation between CSN function and LA volume in 48 symptomatic patients with severe AS (median age: 85 years, IQR 82-88 years; 81% female) before and after TAVR. CSN function was assessed by performing 123I-metaiodobenzylguanidine (MIBG) scintigraphy before and 6 months after TAVR, and the delayed heart-to-mediastinum ratio (dHMR) and washout rate (WR) were calculated. We also performed transthoracic echocardiography near the same time. TAVR improved the dHMR, WR, and LA volume index (LAVI) (dHMR: median 2.89 [IQR 2.62-3.23] vs. 2.98 [2.49-3.25], p = 0.0182; WR: 28% [24-38] vs. 23% [16-32], p < 0.0001; LAVI: 47.7 mL/m2 [37.8-56.3] vs. 41.2 mL/m2 [33.7-56.1], p = 0.0024). In multiple linear regression analysis, the percentage change in LAVI from baseline to post-TAVR (∆LAVI%) was an independent predictor of change in dHMR from baseline to post-TAVR (ß = - 0.35, p = 0.0110). In conclusion, LA volume reduction reflected CSN functional improvement after TAVR. In patients with TAVR, ∆LAVI% might be a valuable parameter for evaluating CSN functional recovery.
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Estenosis de la Válvula Aórtica , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Femenino , Anciano de 80 o más Años , Masculino , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Resultado del Tratamiento , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/cirugía , Atrios Cardíacos , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Patients with epidermal growth factor receptor (EGFR)-mutated, advanced non-small cell lung cancer have received immunochemotherapy as one of the treatment options after tyrosine kinase inhibitor (TKI) failure. METHODS: We retrospectively examined EGFR-mutant patients treated with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) therapy or platinum-based chemotherapy (Chemo) after EGFR-TKI therapy at five institutions in Japan. RESULTS: A total of 57 patients with EGFR mutation were analyzed. The median progression-free survival (PFS) and overall survival (OS) in the ABCP (n = 20) and Chemo (n = 37) were 5.6 and 20.9 months, 5.4 and 22.1 months, respectively (PFS, p = 0.39; OS, p = 0.61). In programmed death-ligand 1 (PD-L1)-positive patients, median PFS in the ABCP group was longer than in the Chemo group (6.9 vs. 4.7 months, p = 0.89). In PD-L1-negative patients, median PFS in the ABCP group was significantly shorter than in the Chemo group (4.6 vs. 8.7 months, p = 0.04). There was no difference in median PFS between the ABCP and Chemo groups in the subgroups of brain metastases, EGFR mutation status, or chemotherapy regimens, respectively. CONCLUSION: The effect of ABCP therapy and chemotherapy was comparable in EGFR-mutant patients in a real-world setting. The indication for immunochemotherapy should be carefully considered, especially in PD-L1-negative patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , 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/patología , Estudios Retrospectivos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Antígeno B7-H1 , Resultado del Tratamiento , Receptores ErbB , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoAsunto(s)
Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Humanos , Sirolimus , Proyectos Piloto , Polímeros , Implantes Absorbibles , Troponina , Resultado del Tratamiento , Intervención Coronaria Percutánea/efectos adversos , Diseño de Prótesis , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapiaRESUMEN
BACKGROUND: Excimer laser coronary angioplasty (ELCA) has been reported to be a safe and effective atherectomy device in percutaneous coronary intervention (PCI). However, thrombotic complications after ELCA have been occasionally observed. In this study, we evaluated the impact of attenuated plaque on thrombus formation and transient no-reflow after ELCA. METHODS: This study enrolled 58 lesions in 56 patients who underwent PCI with ELCA. It was a retrospective observational study at a single center. All lesions were imaged by intravascular ultrasound (IVUS) before and immediately after ELCA. On the plaque with ultrasound attenuation, attenuation angle per millimeter and attenuation length were measured. ELCA-induced thrombus was detected by IVUS, and transient no-reflow after ELCA was recorded. RESULTS: Thrombus was detected in 14 lesions (30 %), and transient no-reflow occurred in 3 lesions (5 %). Lesions with thrombus had a higher mean attenuation angle (median [interquartile range] 142° [112°-152°] vs. 64° [0°-115°]; p = 0.001), maximum attenuation angle (209° [174°-262°] vs. 86° [0°-173°]; p < 0.001), and longer attenuation length (12 mm [8 mm-17 mm] vs. 2 mm [0 mm-5 mm]; p < 0.001). Lesions with thrombus leading to transient no-reflow had a longer lipid length and a significantly higher troponin I level after PCI. CONCLUSIONS: IVUS-identified attenuated plaque was strongly correlated with ELCA-induced thrombus. Furthermore, attenuation length may predict transient no-reflow.
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Aterectomía Coronaria , Enfermedad de la Arteria Coronaria , Intervención Coronaria Percutánea , Placa Aterosclerótica , Trombosis , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/complicaciones , Intervención Coronaria Percutánea/efectos adversos , Láseres de Excímeros/efectos adversos , Angiografía Coronaria , Resultado del Tratamiento , Ultrasonografía IntervencionalRESUMEN
PURPOSE: The effect of immuno-chemotherapy on patients with advanced non-small-cell lung cancer (NSCLC) harboring oncogenic mutations remains poorly understood. This study aimed to characterize the efficacy of immuno-chemotherapy and determine the optimal treatment strategy for such patients. METHODS: We conducted this retrospective cohort study on patients with NSCLC harboring oncogenic driver alterations and treated with an immune checkpoint inhibitor combined with chemotherapy at five institutions. The clinical characteristics and outcomes of immuno-chemotherapy for NSCLC with oncogenic mutations in a real-world setting were analyzed. RESULTS: Among 846 patients diagnosed with advanced or recurrent NSCLC between April 2017 and April 2021, 43 patients with oncogenic mutations were treated with immuno-chemotherapy. The median age of patients was 68 (range 44-78) years; 42% of patients never smoked, and adenocarcinoma was the most common histology (95%). In patients with KRAS mutations (n = 10) or PD-L1 expression of 50% or greater (n = 10), the disease control rate was 100%. The median progression-free survival (PFS) was 5.4, 6.3, and 8.9 months in patients harboring mutations in EGFR, KRAS, and other genes, respectively (P = 0.22). Patients with PD-L1 expression of 50% or greater had significantly longer median PFS than patients with PD-L1 expression of less than 50% (16.4 vs. 5.1 months; P = 0.001). Two patients experienced grade 3 immuno-related adverse events. CONCLUSION: Immuno-chemotherapy has a clinical benefit and is safe for patients with oncogenic mutations. Notably, patients with PD-L1 expression of 50% or more experience greater benefit from immuno-chemotherapy than those with PD-L1 expression of less than 50%.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Adulto , Persona de Mediana Edad , Anciano , 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 , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Antígeno B7-H1 , Estudios Retrospectivos , Proteínas Proto-Oncogénicas p21(ras)/genética , Recurrencia Local de Neoplasia , MutaciónRESUMEN
A coherent Doppler LIDAR (CDL) with long-duration frequency-modulated pulses was demonstrated and validated by analyzing the data observed by a prototype. In traditional CDL using short-duration single-frequency pulses (PCDL; pulsed CDL), there exists a trade-off relationship between distance and velocity resolution. Meanwhile, in earlier work, a theoretical framework of CDL using long-duration frequency-modulated pulses (FMCDL; frequency-modulated CDL) was put forth to eliminate the trade-off. We developed the prototype to be operated as both a PCDL and FMCDL. Analyses of data observed by the PCDL and FMCDL modes showed that the FMCDL worked in good agreement with the PCDL for wind ranging and velocimetry. Furthermore, the performance of the FMCDL in terms of received power and resolution of distance and velocity was quantitatively consistent with ones theoretically expected.
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Introduction: To date, the efficacy and safety of programmed death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy for patients with extensive-stage SCLC (ES-SCLC), with real-world evidence, stratified on the basis of age and performance status (PS), have not been fully investigated. The aim of this study was to evaluate the efficacy and safety of PD-L1 inhibitor plus platinum-etoposide chemotherapy in patients with ES-SCLC. Methods: This multicenter prospective study evaluated patients with ES-SCLC who received PD-L1 inhibitor plus platinum-etoposide chemotherapy between September 2019 and October 2021. Results: A total of 45 patients with ES-SCLC received the aforementioned treatment, including 18 elderly (≥75 y old) patients and six patients with a PS of 2. Multivariate analysis indicated that a PS of 2 was a significant independent prognostic factor for progression-free survival and overall survival (p = 0.008 and p = 0.001, respectively). Of patients with PS of 2 at the initial phase, those that achieved PS improvement during treatment had significantly longer progression-free survival and overall survival than those who did not (p = 0.02 and p = 0.02, respectively). The incidence of adverse events accompanied with treatment discontinuation was significantly higher in the elderly patients than in the non-elderly patients (p = 0.03). Conclusions: This real-world prospective study found that PD-L1 inhibitor plus platinum-etoposide chemotherapy had limited efficacy in patients with ES-SCLC with a PS of 2, except for cases with improvement of PS during treatment. Owing to the emergence of adverse events and treatment discontinuation, this treatment should be administered with caution in elderly patients with ES-SCLC.
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Pulmonary pleomorphic carcinoma (PPC) is well-known for its aggressive nature that is usually resistant to platinum-based chemotherapy. On the other hand, the efficacy of an immune checkpoint inhibitor-based regimen in PPC has been elucidated. PPCs harboring epidermal growth factor receptor (EGFR) mutations are extremely rare, and the efficacy of EGFR-tyrosine kinase inhibitors in PPC is limited compared to their efficacy in EGFR-mutated adenocarcinoma. A 43-year-old female patient presenting with a lung mass with multiple brain metastases, carcinomatous pericarditis, and multiple bone metastases was referred to our department. Transbronchial biopsy confirmed the diagnosis of PPC harboring an EGFR mutation with exon 19 deletion. Subsequently, she was treated with osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, which resulted in partial response with shrinkage of the primary lesion and brain metastases. This partial response remained durable for 11 months with an ongoing regimen. The current case suggests that osimertinib would show promising effects as a first-line treatment for PPCs harboring EGFR mutations, as well as a reasonable sequence of therapy followed by immune checkpoint inhibitor-based regimens.
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Adenocarcinoma , Antineoplásicos , Neoplasias Encefálicas , Neoplasias Pulmonares , Acrilamidas , Adenocarcinoma/tratamiento farmacológico , Adulto , Compuestos de Anilina , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Receptores ErbB/genética , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico , Indoles , Pulmón/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , PirimidinasRESUMEN
Large-cell neuroendocrine carcinomas (LCNECs), categorized as high-grade neuroendocrine carcinomas, account for approximately 3% of resected lung cancers. LCNECs containing other components are called 'combined LCNECs' and have no standard treatment. A 73-year-old male with a metastatic brain tumour from a combined LCNEC of the lung containing adenocarcinoma and sarcomatoid components was referred to our department. The patient was treated with chemotherapy consisting of carboplatin and nanoparticle albumin-bound (nab)-paclitaxel in combination with atezolizumab, which was decided in accordance with the histological evaluation of the components. This treatment resulted in partial response and remained durable for 12 months with an ongoing regimen. The current case suggests that the constituents of chemoimmunotherapy should be selected in accordance with the reported efficacy of relevant regimens for each component of the combined LCNEC.
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P-wave terminal force in lead V1 (PTFV1) is a marker of increased left atrial (LA) overload. Whether PTFV1 is associated with left ventricular (LV) diastolic function remains undetermined. We tested the hypothesis that PTFV1 is associated with LV diastolic parameters derived from gated myocardial perfusion single-photon emission computed tomography (SPECT) in patients with no significant perfusion abnormalities.The study population included 158 patients with preserved ejection fraction and no significant perfusion abnormalities. The amplitude and duration of the P-wave negative phase in lead V1 were measured using an electrocardiogram, and PTFV1 was calculated. The peak filling rate (PFR) and one-third mean filling rate (1/3 MFR) were obtained as LV diastolic parameters using gated SPECT.PTFV1 showed a weak correlation with the LA volume index (r = 0.31; P < 0.001). Significant associations were observed between PTFV1 and PFR (r = -0.27; P < 0.001) and 1/3 MFR (r = -0.26; P = 0.001). A multivariate linear regression analysis showed that age (ß = -0.26; P < 0.001), LV end-diastolic volume index (ß = -0.27; P = 0.001), and PTFV1 (ß = -0.15; P = 0.036) were significant factors associated with PFR. Moreover, male gender (ß = -0.16; P = 0.041), LV mass index (ß = -0.17; P = 0.046), and PTFV1 (ß = -0.17; P = 0.022) were significant factors associated with the 1/3 MFR.PTFV1 is associated with LV diastolic function, as derived from gated SPECT in patients with no significant perfusion abnormalities.
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Tomografía Computarizada de Emisión de Fotón Único , Función Ventricular Izquierda , Diástole , Humanos , Masculino , Perfusión , Volumen Sistólico , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
BACKGROUND: The optimal dosage for cryoballoon ablation (CBA) of atrial fibrillation (AF) is still unknown. OBJECTIVE: This study aimed to evaluate the clinical implications of a reduction in the freezing duration to <180 seconds during CBA guided by the time to the target temperature. METHODS: This study enrolled 325 consecutive paroxysmal AF patients who underwent CBA. It was a retrospective observational study in a single centre. It compared 164 patients who underwent a tailor-made CBA procedure (group T) with 161 who had a standard CBA procedure (group S). In group T, the freezing duration was reduced to 150 seconds when the temperature reached ≤ -40 °C within 40 seconds. Furthermore, it was reduced to 120 seconds when it reached ≤ -50 °C within 60 seconds. In the other patients, the freezing duration was 180 seconds, except for excessive freezing of ≤ -60 °C and/or emergent situations while monitoring the oesophageal temperature, and for phrenic nerve injury, as in group S. RESULTS: In group T, 89 patients (83%) underwent CBA with a reduction in the freezing duration. The total freezing time for each pulmonary vein was significantly shorter in group T than group S, and the total procedure time in group T decreased by an average of 4 minutes compared with group S. The rate of requiring additional radio frequency ablation following the CBA was significantly lower in group T than group S. The AF-free survival rate during the follow-up period (median, 366 days) was similar between the two groups. CONCLUSION: The safety and efficacy of the new CBA strategy were non-inferior to the standard procedure.
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Fibrilación Atrial , Ablación por Catéter , Criocirugía , Venas Pulmonares , Fibrilación Atrial/cirugía , Ablación por Catéter/métodos , Criocirugía/métodos , Humanos , Venas Pulmonares/cirugía , Recurrencia , Resultado del TratamientoRESUMEN
PURPOSE: Pulmonary vein (PV) isolation using balloon ablation was developed as a technique for patients with paroxysmal atrial fibrillation (PAF). While most studies examined cryoballoon ablation (CBA), there have also been many reports on hot balloon ablation (HBA). We aimed to evaluate the clinical characteristics and outcomes between HBA and CBA. METHODS: In a total of 103 consecutive patients with PAF who underwent catheter ablation, 60 propensity score-matched (30 CBA and 30 HBA) patients were enrolled. The procedural differences and clinical outcomes between the two groups were analyzed. RESULTS: The requirement for additional touch-up ablation was more frequent in the left superior pulmonary vein (LSP) in the HBA group than in the CBA group. Pre-procedural computed tomography (CT) images showed that a thicker left pulmonary vein ridge and larger cross-sectional area of the LSPV were significantly associated with residual PV potentials after HBA. However, post-procedural CT images showed that PV stenosis (> 25%) was higher in the HBA group (33%) than in the CBA group (0%). PV stenosis after HBA was observed most frequently in the right superior PV (50%). The atrial fibrillation/atrial tachycardia-free survival rate during follow-up (365 ± 102 days) was similar between the two groups (CBA vs. HBA, 83% vs. 90%). CONCLUSIONS: Although both balloon modalities can relieve atrial arrhythmia after the procedure, careful attention is required during HBA procedures, especially for the right superior PV, to avoid PV stenosis.
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Fibrilación Atrial , Ablación por Catéter , Criocirugía , Venas Pulmonares , Estenosis de Vena Pulmonar , Fibrilación Atrial/diagnóstico por imagen , Fibrilación Atrial/cirugía , Constricción Patológica , Criocirugía/métodos , Humanos , Venas Pulmonares/diagnóstico por imagen , Venas Pulmonares/cirugía , Factores de Riesgo , Estenosis de Vena Pulmonar/cirugía , Factores de Tiempo , Resultado del TratamientoRESUMEN
An esophageal stricture is an abnormal esophageal narrowing, usually caused by esophageal diseases and rarely by lung cancer. They cause malnutrition, performance status (PS) deterioration, and difficulty in the oral administration of antitumor drug tablets. A 78-year-old female patient with lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR)-sensitizing mutation, experienced dysphagia due to an esophageal stricture caused by retrotracheal lymph node metastases. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor that is efficacious against EGFR-sensitizing mutations. The esophageal stricture hampered food intake and oral administration of osimertinib, causing severe malnutrition and deterioration to PS 3. Esophagogastroduodenoscopy (EGD) revealed severe and entire circumferential stenosis (7 cm in length) of the upper esophagus without mucosal abnormality. A nasogastric tube was inserted under EGD guidance, and an osimertinib suspension was administered accordingly: a tablet containing 80 mg of osimertinib was suspended in 50 mL of sterile hot water (55 â) for ten minutes, and the suspension was administered through a nasogastric tube once daily. Dysphagia improved 15 days after the introduction of osimertinib. After 21 days, the patient could take foods and drugs orally, and her PS improved to 1. Administering an osimertinib suspension via a nasogastric tube was a viable option in managing esophageal strictures in patients with EGFR-sensitizing mutations.
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Carcinoma de Pulmón de Células no Pequeñas , Trastornos de Deglución , Estenosis Esofágica , Neoplasias Pulmonares , Desnutrición , Acrilamidas , Anciano , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas/genética , Trastornos de Deglución/etiología , Receptores ErbB/genética , Estenosis Esofágica/etiología , Femenino , Humanos , Neoplasias Pulmonares/patología , MutaciónRESUMEN
The prognoses of patients with non-small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangement have dramatically improved with the use of ALK tyrosine kinase inhibitors. Although immunological and nutritional markers have been investigated to predict outcomes in patients with several cancers, their usefulness in targeted therapies is scarce, and their significance has never been reported in patients receiving first-line treatment with alectinib. Meanwhile, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (PLR) has been investigated during crizotinib treatment. This multicenter retrospective study evaluated 42 consecutive Japanese patients with ALK-positive NSCLC who received first-line treatment with alectinib. Immunological and nutritional markers were evaluated at baseline and 3 weeks after alectinib introduction, and their significance in predicting progression-free survival (PFS) was explored. PFS duration was significantly associated with baseline PLR (hazard ratio (HR): 2.49, p = 0.0473), systemic immune-inflammation index (SII; HR: 2.65, p = 0.0337), prognostic nutrition index (PNI; HR: 4.15, p = 0.00185), and the 3-week values for SII (HR: 2.85, p = 0.0473) and PNI (HR: 3.04, p = 0.0125). Immunological and nutritional markers could be useful in predicting the outcomes of first-line treatment with alectinib. Since PLR and SII consist of platelet counts, platelet count could be an important constituent of these markers.
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Chromosomal rearrangements involving the c-ros oncogene 1 (ROS1) are identified in approximately 1% of non-small cell lung cancer (NSCLC) patients. Crizotinib is the first tyrosine kinase inhibitor (TKI) against ROS1-rearranged NSCLC. G2032R, a secondary resistant mutation, is observed in 41% of patients treated with crizotinib. Entrectinib, a TKI against neurotrophic tropomyosin receptor kinase, is reportedly efficacious against ROS1-rearranged NSCLC. However, ROS1-G2032R is resistant to entrectinib both in vitro and in vivo. We report an 85-year-old female patient with ROS1-rearranged NSCLC, who developed drug-induced interstitial lung disease (DI-ILD) 2 months after crizotinib treatment, and was treated with prednisolone followed by entrectinib. Entrectinib treatment resulted in stable disease with a marginal response after a partial response to crizotinib. Entrectinib treatment following crizotinib cessation due to DI-ILD was efficacious, which suggested that ROS1-G2032R gatekeeper mutation, frequently observed in crizotinib-resistant disease, was absent.
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Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC) harboring ALK- rearrangements. However, a small population of tumor cells survives due to adaptive resistance under drug pressure and ultimately acquires drug resistance. Thus, it is necessary to elucidate the mechanisms underlying the prevention of drug resistance to improve the prognosis of patients with ALK-rearranged NSCLC. We identified novel adaptive resistance, generated through c-Jun N-terminal kinase (JNK)/c-Jun signaling, to initial ALK-TKIs-alectinib and brigatinib-in ALK-rearranged NSCLC. Inhibition of JNK/c-Jun axis showed suppression of growth and promotion of apoptosis induced by ALK-TKIs in drug-tolerant cells. JNK inhibition, in combination with the use of ALK-TKIs, increased cell apoptosis through repression of the Bcl-xL proteins, compared with ALK-TKI monotherapy. Importantly, combination therapy targeting JNK and ALK significantly delayed the regrowth following cessation of these treatments. Together, our results demonstrated that JNK pathway activation plays a pivotal role in the intrinsic resistance to ALK-TKIs and the emergence of ALK-TKI-tolerant cells in ALK-rearranged NSCLC, thus indicating that optimal inhibition of tolerant signals combined with ALK-TKIs may potentially improve the outcome of ALK-rearranged NSCLC.
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Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Inhibidores de Proteínas Quinasas/farmacología , Animales , Apoptosis/efectos de los fármacos , Carbazoles/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Reordenamiento Génico/efectos de los fármacos , Xenoinjertos , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Ratones , Análisis por Micromatrices , Compuestos Organofosforados/farmacología , Piperidinas/farmacología , Proteoma/genética , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Proteína bcl-X/genéticaRESUMEN
Chemoimmunotherapy has become the standard of care as the first-line treatment of advanced or recurrent non-small-cell lung cancer (NSCLC). The bevacizumab-containing chemoimmunotherapy regimen is theoretically more effective than a non-bevacizumab-containing regimen via two mechanisms: a superior outcome of bevacizumab-containing chemothrerapy than the standard platinum doublet regimen, and the synergistic effect of bevacizumab with an immune checkpoint inhibitor (ICI). Bevacizumab effectively normalizes vascularization, especially when the vascular bed is damaged by previous treatment. Bevacizumab promotes immunomodulation when used with ICI. We describe a patient with nonsquamous NSCLC who returned 2.5 years after definitive chemoradiotherapy for postoperative locoregional recurrence in the right supraclavicular lymph node. Considering the destroyed vascular bed due to prior chemoradiotherapy, attaining vascular normalization was critical for effective drug delivery. The patient was treated with a bevacizumab-containing chemoimmunotherapy regimen, which resulted in a complete metabolic response. The patient responded well for 23 months and is receiving ongoing treatment. Thus, bevacizumab-containing chemoimmunotherapy could be advantageous in some recurrent cases after chemoradiotherapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Quimioradioterapia , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
ObjectivesãThe number of elderly joggers/runners in Japan has been on the rise. This study aimed to investigate the practice of jogging/running activity, features of quality of life (QOL) among the elderly, and the relationships between jogging/running activity and QOL features.MethodsãA questionnaire survey was conducted with 83 older adults aged 60-81 who had participated in 7 marathons held from November 2014 to July 2015. Sex, age, experience (years), mileage (kms/month), frequency of jogging/running activity (times/week), frequency of participation in marathons (times/year), and QOL were assessed. QOL was measured with the WHOQOL26, which is composed of "overall QOL", "physical," "psychological," "social relationships," and "environment." The relations between these variables were estimated using correlation and multiple regression analyses.ResultsãIn the majority of the participants, experience was 5 or more years, mileage was less than 150 kms/month, frequency of jogging/running activity was 1-4 times a week, and frequency of participation in marathons was 1-10 times a year. As for the participants above the age of 65, the mean QOL for men was 3.8 (standard deviation (SD)=0.4) and for women was 4.1 (SD=0.5). These scores were higher than those previously reported in studies among Japanese older adults. And there was no evidence which showed the bodily pain such as lower limb disorders, which older joggers or runners may often get. Overall QOL was positively associated with age and frequency of jogging/running activity. The social relationships domain was positively associated with sex and experience. The environment domain was positively correlated with experience. All these associations were significant.ConclusionsãThe results suggest that among the elderly, a high frequency and/or experience of jogging/running activity is significantly associated with a high level of QOL. In the future, a case-control or longitudinal study with a larger sample size and/or more variables is required to obtain a more definitive interpretation of the present findings.