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1.
Cancer Sci ; 113(6): 2109-2117, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35377496

RESUMEN

It is not clear whether pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) should be selected for patients with advanced non-small-cell lung cancer (NSCLC) exhibiting high PD-L1 expression (tumor proportion score ≥ 50%). We performed a retrospective, multicenter study of 300 patients with NSCLC exhibiting high PD-L1 expression who received MONO or COMB as first-line treatment between December 2018 and January 2020. We reviewed the medical records of all consecutive patients with no driver mutations, and assessed the patient characteristics, therapeutic regimens, treatment periods, and adverse events. In total, 166 (55%; median age: 74 years) and 134 (45%; median age: 68 years) patients received MONO and COMB, respectively. Patients were younger and had better performance status (0-1) in the COMB group (p < 0.01). With a median follow-up time of 10.6 (range: 0.1-20.6) months, the median progression-free survival was 7.1 months with MONO and 13.1 months with COMB. The objective response rate was 42.2% with MONO and 67.9% with COMB. With respect to treatment discontinuation, 36 out of 166 (21.7%) and 28 out of 134 (20.1%) patients discontinued MONO and COMB, respectively. In conclusion, COMB may be a promising option for first-line treatment for NSCLC with high PD-L1 expression and good performance status.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1/metabolismo , 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 , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Estudios Multicéntricos como Asunto , Estudios Retrospectivos
2.
Int J Clin Oncol ; 22(1): 59-69, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27553958

RESUMEN

BACKGROUND: The Notch receptor plays an important role in various cell fate decisions during development and in cancer. We have previously reported that Notch3 is upregulated by radiation in non-small cell lung cancer (NSCLC) cell lines and that the Notch pathway inhibitor γ secretase inhibitor GSI (gamma-secretase inhibitor), when combined with radiation therapy, significantly suppressed the growth of lung cancer cells. However, little is known about the mechanism of Notch upregulation induced by radiation. Based on reports of Notch expression being activated through the hypoxia inducible factor 1 (HIF-1) under hypoxic conditions, we hypothesized that HIF-1 would be involved in radiation-induced Notch activation in NSCLC. METHODS: Changes in HIF-1 and Notch expression in two Notch expressing NSCLC cells line after radiation treatment were examined using Western blotting. Notch expression was evaluated after the suppression of HIF-1α by small interfering RNA. The cytotoxic effect of YC-1, a HIF inhibitor, GSI and radiation was examined using the MTT assay in vitro and the xenograft model. RESULT: We found radiation-induced expression of HIF-1α protein at 2-6 h after treatment and upregulated expression of Notch3 protein at 24 h after treatment under hypoxic conditions. Specific suppression of HIF-1α expression downregulated the radiation-induced Notch3 activation, suggesting that the Notch pathway is activated though HIF-1α after radiation. An antitumor effect of YC-1 was evident under hypoxic conditions only when there was simultaneous radiation treatment. GSI and YC-1 had a synergistic antitumor effect in vitro, and the combination of GSI and YC-1 showed the greatest radiosensitivity in vivo. CONCLUSION: Radiation-induced upregulation of the Notch pathway and HIF-1α protein may be potential therapeutic targets for more effective radiation therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Neoplasias Pulmonares/radioterapia , Receptores Notch/antagonistas & inhibidores , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/efectos de la radiación , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/efectos de la radiación , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Indazoles/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones Desnudos , Terapia Molecular Dirigida/métodos , Oligopéptidos/farmacología , ARN Interferente Pequeño , Receptores Notch/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Int J Clin Oncol ; 22(2): 257-268, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27816990

RESUMEN

BACKGROUND: Inhibition of Notch by γ-secretase inhibitor (GSI) has been shown to have an antitumor effect in Notch-expressing non-small cell lung cancer (NSCLC) and to induce apoptosis through modulation of Bcl-2 family proteins. In particular, Bim, a BH3-only member of the Bcl-2 family of proteins, has an important role in the induction of apoptosis in NSCLC when cells are treated with GSI. ABT-737, a BH3-only mimetic, targets the pro-survival Bcl-2 family and also induces apoptosis. METHODS: The Notch-expressing NSCLC cell lines H460, A549, H1793, and HCC2429 were used. The combined antitumor effect of GSI and ABT-737 was evaluated using the MTT proliferation assay in vitro and in xenograft mouse models. The expression of the Notch pathway and Bcl-2 family was analyzed using Western blotting analysis when cells were treated with a single drug treatment or a combination treatment. RESULTS: GSI XX or ABT-737 alone inhibited cell proliferation in a dose-dependent manner, and combination drug treatment showed a synergistic antitumor effect in vitro. In vivo, this drug combination significantly suppressed tumor proliferation compared to the single drug treatment. Phospho-Bcl-2 was downregulated and Bax was upregulated by both the single and combination drug treatments. Bim was induced by a single drug treatment and was enhanced by combination treatment. Combination treatment-induced apoptosis was decreased by Bim inhibition, suggesting that the antitumor effect of the drug combination was dependent on Bim. CONCLUSION: Based on our data, we propose that the combination treatment is a promising strategy for NSCLC therapy.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Dibenzazepinas/farmacología , Neoplasias Pulmonares/patología , Nitrofenoles/farmacología , Sulfonamidas/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Quimioterapia Combinada , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Desnudos , Piperazinas/farmacología , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Respiration ; 88(2): 137-43, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24993187

RESUMEN

BACKGROUND: Ground-glass opacity (GGO) lesions are difficult to diagnose by transbronchial biopsy (TBB). OBJECTIVES: We attempted to diagnose solitary peripheral GGO predominant-type lesions by TBB using endobronchial ultrasonography with a guide sheath (EBUS-GS) under X-ray fluoroscopic guidance, and to evaluate several factors associated with diagnostic yield. METHODS: The medical records of 67 patients with GGO predominant-type lesions who underwent TBB using EBUS-GS under X-ray fluoroscopic guidance were retrospectively reviewed. RESULTS: Of the 67 lesions, 38 (57%) were successfully diagnosed by EBUS-GS (5/11 pure GGO lesions and 33/56 mixed GGO lesions). The diagnosable lesions were significantly larger than the nondiagnosable lesions (24 vs. 17 mm, respectively; p < 0.01). Regarding the diagnostic yield by signs on computed tomography, the lesions with a bronchus leading directly to a lesion had a significantly higher diagnostic yield than the others (p < 0.05). When GGO lesions were confirmed under X-ray fluoroscopic guidance, the diagnostic yield was 79% (vs. 40% in lesions not visible on X-ray fluoroscopy; p < 0.05). CONCLUSIONS: EBUS-GS is a useful and valuable diagnostic modality, even for GGO predominant-type lesions located at the lung periphery.


Asunto(s)
Adenocarcinoma/diagnóstico , Broncoscopía , Neoplasias Pulmonares/diagnóstico , Ultrasonografía Intervencional , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fluoroscopía , Humanos , Pulmón/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Adulto Joven
5.
Cancer Med ; 13(14): e70036, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39030894

RESUMEN

BACKGROUND: Selecting pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) for patients with nonsmall cell lung cancer (NSCLC) and high programmed death-ligand 1 (PD-L1) expression is an important issue in clinical practice. We previously conducted a retrospective multicenter observational study of patients with NSCLC and high PD-L1 expression who received MONO or COMB as a first-line treatment. Here, we report updated data and evaluate the long-term outcomes. METHODS: We performed a retrospective multicenter study of 298 patients with NSCLC and high PD-L1 expression who received MONO or COMB as first-line treatment between December 2018 and January 2020. We reviewed the medical records and assessed the clinical efficacy and toxicity using a prolonged data cutoff. RESULTS: In total, 164 (median age: 74 years) and 134 (median age: 68 years) patients received MONO and COMB, respectively; patients who received COMB were younger and had better performance statuses (0-1). At the prolonged data cutoff, the median follow-up was 20.2 (range: 0.1-41.4) months. The median progression-free survivals were 7.5 and 13.1 months, and overall survivals (OSs) were 17.2 and 33.7 months for MONO and COMB, respectively. Treatment discontinuation rates were 21.9% and 20.1% for the MONO and COMB, respectively. With prolonged follow-up, although COMB demonstrated an OS benefit and higher objective response rate than MONO, in the propensity score matching analysis COMB didn't demonstrate a significant benefit compared to the MONO. CONCLUSIONS: COMB may be effective as a first-line treatment for NSCLC with high PD-L1 expression in a selected subset of patients.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Antígeno B7-H1 , 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/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/metabolismo , Femenino , Anciano , Antígeno B7-H1/metabolismo , Estudios Retrospectivos , Persona de Mediana Edad , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Resultado del Tratamiento , Antineoplásicos Inmunológicos/uso terapéutico
6.
Sci Rep ; 11(1): 23140, 2021 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-34848786

RESUMEN

Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1-73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9-23.9) months. The median overall survival was not reached (95% confidence interval 24.6-not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.


Asunto(s)
Acrilamidas/farmacología , Compuestos de Anilina/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Mutación , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Receptores ErbB/genética , Exones , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Oncogenes , Pronóstico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento
7.
Mol Clin Oncol ; 13(1): 43-47, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32499913

RESUMEN

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare type of lung cancer, accounting for 3% of all lung cancers. The prognosis is poor and the standard therapy has not been well established. Herein, we report a case of advanced LCNEC of the lung that responded to nivolumab. The patient was a 62-year old man with stage IVB LCNEC of the lung. The disease progressed following the administration of second-line chemotherapy, and he was treated with nivolumab 3 mg/kg as the third-line treatment. Although treatment was ceased after two cycles due to interstitial pneumonia, the disease remained stable for approximately six months under observation. There was no other adverse event related to nivolumab. Following patient mortality from tumor progression, PD-L1 expression was observed to be negative (tumor proportion score <1%) by a re-examination of the primary biopsy specimen. The case herein suggests that nivolumab may be a possible treatment option for LCNEC.

8.
Nihon Kokyuki Gakkai Zasshi ; 47(8): 727-30, 2009 Aug.
Artículo en Japonés | MEDLINE | ID: mdl-19764517

RESUMEN

A 50-year-old man was referred and admitted to our hospital because of pneumonia and pleuritis. The patient had attempted suicide by inhaling automobile exhaust 3 years ago. Carbon monoxide intoxication had caused persistent disturbance of consciousness and quadriplegia. He had been tracheostomised and under nutrition by percutaneous endoscopic gastrostomy. On admission the presence of left pleural fluid with thickening of the pleura was shown on computed tomography. Thoracocentesis produced suppurative fluid with Actinomyces species nova identified by the 16S rRNA method. The patient was successfully treated with antibiotics and drainage of suppurative fluid.


Asunto(s)
Actinomyces/aislamiento & purificación , Empiema/microbiología , Humanos , Masculino , Persona de Mediana Edad , Intento de Suicidio
9.
Intern Med ; 57(12): 1769-1772, 2018 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-29434159

RESUMEN

This report describes the case of a 66-year-old man with non-small cell lung cancer and venous thromboembolism (VTE). Unfractionated heparin (UFH) was initially used to control VTE before chemotherapy. However, switching UFH to warfarin or edoxaban, a novel oral anticoagulant (NOAC), failed. Chemotherapy was then administered to control the tumor which was thought to have been the main cause of VTE, which had been treated by UFH. After tumor shrinkage was achieved by chemotherapy, we were able to successfully switch from UFH to edoxaban. Controlling the tumor size and activity enabled the use of edoxaban as maintenance therapy for VTE.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Neoplasias Pulmonares/complicaciones , Piridinas/uso terapéutico , Tiazoles/uso terapéutico , Tromboembolia Venosa/complicaciones , Tromboembolia Venosa/tratamiento farmacológico , Anciano , Anticoagulantes/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Heparina/uso terapéutico , Humanos , Neoplasias Pulmonares/patología , Masculino , Carga Tumoral , Warfarina/uso terapéutico
10.
Ann Thorac Surg ; 103(2): 470-475, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27825686

RESUMEN

BACKGROUND: Endobronchial ultrasonography with guide sheath (EBUS-GS) could be useful for diagnosing ground-glass opacity (GGO) predominant-type lesions in the peripheral lung. Furthermore, several studies have reported that transbronchial biopsy using EBUS-GS and virtual bronchoscopic navigation (VBN) was safe and effective for diagnosing small peripheral lung lesions. Our objectives were to diagnose solitary peripheral GGO predominant-type lesions by transbronchial biopsy using EBUS-GS and VBN under radiographic fluoroscopic guidance, and to evaluate the clinical factors associated with diagnostic yield. METHODS: The medical records of 169 patients with GGO predominant-type lesions who underwent transbronchial biopsy using EBUS-GS and VBN under radiographic fluoroscopic guidance were retrospectively reviewed. RESULTS: Endobronchial ultrasonography images could be obtained for 156 (92%) of 169 GGO predominant-type lesions, and 116 (69%) were successfully diagnosed by this method (20 of 31 pure GGO lesions [65%]; 96 of 138 mixed GGO predominant-type lesions [70%]). The mean size of diagnosed lesions was significantly larger than that of nondiagnosed lesions (22 mm versus 18 mm, p < 0.01). Regarding diagnostic yield based on computed tomography sign, cases with presence of a bronchus leading directly to a lesion had significantly higher diagnostic yield than the other lesions (p < 0.01). CONCLUSIONS: The addition of VBN to EBUS-GS could be useful in clinical practice for diagnosing GGO predominant-type lesions in the peripheral lung.


Asunto(s)
Endosonografía/métodos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Ultrasonografía Intervencional/métodos , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Broncoscopía/métodos , Estudios de Cohortes , Femenino , Fluoroscopía/métodos , Hospitales Universitarios , Humanos , Biopsia Guiada por Imagen/métodos , Japón , Masculino , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Estudios Retrospectivos , Factores de Riesgo , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos X/métodos
11.
Cancer Chemother Pharmacol ; 80(5): 955-963, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28905108

RESUMEN

PURPOSE: A high proportion of patients with wild-type EGFR non-small cell lung cancer (NSCLC) receive third-line therapy and beyond, with no prospective randomized trials addressing the issue. This study aimed to select the most suitable regimen as a third- or fourth-line therapy for wild-type EGFR NSCLC. METHODS: This multicenter, randomized phase II study in Japan included patients with recurrent or advanced NSCLC with wild-type or unknown EGFR, who progressed after two or three previous chemotherapies. The patients were randomly assigned to erlotinib (150 mg/day, days 1-21) or S-1 (80-120 mg/day, days 1-14) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR). The secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), toxicity, and quality of life (QOL). RESULTS: From 2011 to 2016, 37 patients were randomly assigned to receive erlotinib (E arm, n = 19) and S-1 (S arm, n = 18). This study was terminated prematurely because of poor patient accrual. DCR/ORR were 42.1%/15.8% in the E arm and 66.7%/16.7% in the S arm. Median PFS/OS were 1.6 months/8.0 months in the E arm and 3.3 months/12.2 months in the S arm. In both groups, the most commonly reported grade 3-4 toxicities were fatigue, anorexia, and nausea. One grade 5 pneumonitis occurred in the S arm. No significant difference was seen in QOL. CONCLUSIONS: S-1 as a third- or fourth-line therapy for wild-type EGFR NSCLC showed numerically better clinical outcomes than erlotinib. CLINICAL TRIAL REGISTRATION NO: UMIN000005308.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Clorhidrato de Erlotinib/administración & dosificación , Clorhidrato de Erlotinib/farmacología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad
13.
Ann Thorac Surg ; 105(5): 1578-1579, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29685238
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