RESUMEN
Purpose: The radiation recall phenomenon (RRP) is a rare and unexpected late complication of radiation therapy (RT). Although predominantly in the skin, RRP of the upper respiratory tract has also been reported. In general, RRP is caused by anticancer agents, and the COVID-19 vaccine has also been reported to cause RRP in recent years. Methods and Materials: A 50-year-old woman who had received RT around the larynx 3 years prior and was receiving a docetaxel + ramucirumab (RAM) regimen experienced recurrent sore throat. The administration of RAM was discontinued after a gastroscopic examination revealed mucosal bleeding from around the larynx, which was thought to be RRP caused by RAM, a vascular endothelial growth factor inhibitor. Results: After the remission of the RRP, the patient received a COVID-19 vaccine (Pfizer-BioNTech). Five days later, the appearance of cough and recurrence of sore throat worsened with time, and marked stridor was observed. The patient was admitted, and steroid pulse therapy was administered for 3 days starting on day 18 after vaccination. On day 50 after vaccination, edema of the vocal cords improved. Conclusions: When administering COVID-19 vaccines, considering that these vaccines may cause RRP is important, because RRP can be fatal in patients with a history of RT in the laryngeal region and treated with vascular endothelial growth factor inhibitors.
RESUMEN
The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a recently identified fusion-type oncoprotein that exists in approximately 5% of non-small cell lung cancer (NSCLC). It has been demonstrated that NSCLC driven by EML4-ALK is strongly addicted to this fusion-type oncokinase. A clinical trial of crizotinib (PF-02341066) sponsored by Pfizer has proven this oncogene addiction in humans by demonstrating a high response rate to inhibition of ALK kinase activity. In the present study, we report on three cases harboring EML4-ALK rearrangement who were enrolled in the trial (A8081001, NCT00585195). All three patients showed favorable responses to the ALK-specific tyrosine kinase inhibitor.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Reordenamiento Génico , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Adulto , Carcinoma de Pulmón de Células no Pequeñas/genética , Crizotinib , Humanos , Neoplasias Pulmonares/genética , MasculinoRESUMEN
CASE: A 72-year-old male had suffered from a recurrent pulmonary squamous cell carcinoma. He had a history of systemic chemotherapy including carboplatin+paclitaxel(CBDCA+PTX)and docetaxel(DOC). As third-line chemotherapy, this patient was treated with 100 mg of S-1 daily for 4 weeks followed by 2 weeks of rest. Maximal effect was acquired 3.5 months after start of S-1 and resulted in partial response. Since tumors re-grew, S-1 was stopped and other chemotherapies including gemcitabine+vinorelbine(GEM+VNR)and gefitinib were tried but proved ineffective. The tumors gradually grew and, subsequently, right total atelectasis occurred. Re-administration of S-1 showed tumor regression and atelectasis improved. Now this patient is continuing treatment with S-1 monotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Ácido Oxónico/uso terapéutico , Tegafur/uso terapéutico , Anciano , Biomarcadores de Tumor , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/diagnóstico por imagen , Combinación de Medicamentos , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/diagnóstico por imagen , Masculino , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
Although responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) are initially positive, 30%-40% of patients with EGFR-mutant tumors do not respond well to EGFR-TKIs, and most lung cancer patients harboring EGFR mutations experience relapse with resistance. Therefore, it is necessary to identify not only the mechanisms underlying EGFR-TKI resistance, but also potentially novel therapeutic targets and/or predictive biomarkers for EGFR-mutant lung adenocarcinoma. We found that the GPI-anchored protein semaphorin 7A (SEMA7A) is highly induced by the EGFR pathway, via mTOR signaling, and that expression levels of SEMA7A in human lung adenocarcinoma specimens were correlated with mTOR activation. Investigations using cell culture and animal models demonstrated that loss or overexpression of SEMA7A made cells less or more resistant to EGFR-TKIs, respectively. The resistance was due to the inhibition of apoptosis by aberrant activation of ERK. The ERK signal was suppressed by knockdown of integrin ß1 (ITGB1). Furthermore, in patients with EGFR mutant tumors, higher SEMA7A expression in clinical samples predicted poorer response to EGFR-TKI treatment. Collectively, these data show that the SEMA7A-ITGB1 axis plays pivotal roles in EGFR-TKI resistance mediated by ERK activation and apoptosis inhibition. Moreover, our results reveal the potential utility of SEMA7A not only as a predictive biomarker, but also as a potentially novel therapeutic target in EGFR-mutant lung adenocarcinoma.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Semaforinas/genética , Semaforinas/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Integrina beta1/genética , Neoplasias Pulmonares , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos BALB C , Mutación , Células 3T3 NIH , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
EGFR is involved in the density-dependent inhibition of cell growth, while coexpression of EGFR with erbB2 can render normal cells transformed. In this study, we have examined the effect of a species of p185 that contains the transmembrane domain and the extracellular domain of p185(c-neu), on growth properties of a human malignant mesothelioma cell line that coexpresses EGFR and erbB2. The ectodomain form of p185(c-neu) enhanced density-dependent inhibition of cell growth and we found that p21 induction appeared to be responsible for this inhibitory effect. Previously, the extracellular domain species was shown to suppress the transforming abilities of EGFR and p185(c-neu/erbB2) in a dominant-negative manner. The ability of this subdomain to affect tumor growth is significant, as it reduced in vivo tumor growth. Unexpectedly, we found that the domain did not abrogate all of EGFR functions. We noted that EGFR-induced density-dependent inhibition of cell growth was retained. Tyrosine kinase inhibitors of EGFR did not cause density-dependent inhibition of cell growth of malignant mesothelioma cells. Therefore, simultaneously inhibiting the malignant phenotype and inducing density-dependent inhibition of cell growth in malignant mesothelioma cells by the extracellular domain of p185(c-neu) may represent an important therapeutic advance.
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Mesotelioma/genética , Mesotelioma/patología , Receptor ErbB-2/genética , Animales , Línea Celular Tumoral , Proliferación Celular , Receptores ErbB/genética , Fase G1 , Expresión Génica , Genes erbB-2 , Humanos , Mesotelioma/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Biológicos , Trasplante de Neoplasias , Estructura Terciaria de Proteína , Receptor ErbB-2/química , Receptor ErbB-2/fisiología , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transfección , Trasplante HeterólogoRESUMEN
Coccidioidomycosis, caused by inhaling Coccidioides immitis, is a mycosis imported from endemic regions including the southwestern United States. C. immitis is so virulent that even a short-term stay in the endemic area can provide a chance for infection. Here, we report a 33-year-old Japanese man with formation of a fungus ball inside the pulmonary cavity secondary to coccidioidomycosis with a duration of 8 years, which is considered rare. He was infected with C. immitis in the United States in 1996. A nodule remained in the lung, which later cavitated with fungus ball formation. We identified Coccidioides immitis in the cultured specimen from the cavity and serum antibodies against it. We performed a lobectomy in 2003 since anti-fungal treatment was only temporarily effective. He is still free of disease 6 months later.
Asunto(s)
Coccidioidomicosis/microbiología , Enfermedades Pulmonares Fúngicas/microbiología , Adulto , Anticuerpos Antifúngicos/análisis , Antifúngicos/uso terapéutico , Broncoscopía , Coccidioides/inmunología , Coccidioides/aislamiento & purificación , Coccidioidomicosis/diagnóstico , Coccidioidomicosis/terapia , Diagnóstico Diferencial , Estudios de Seguimiento , Humanos , Pulmón/microbiología , Enfermedades Pulmonares Fúngicas/diagnóstico , Enfermedades Pulmonares Fúngicas/terapia , Masculino , Neumonectomía , Radiografía Torácica , Tomografía Computarizada por Rayos XRESUMEN
Small-cell lung cancer (SCLC) easily recurs with multidrug resistance phenotype. However, standard therapeutic strategies for relapsed-SCLC remain unestablished. Human epidermal growth factor receptor 2 (HER2) expression correlates with poor prognosis in extensive disease-SCLC. We have reported previously that HER2 expression is upregulated when HER2-positive SCLC cells acquire chemoresistance, and also demonstrated that trastuzumab exerts significant antitumor activity toward HER2-upregulated chemoresistant SCLC, mainly via antibody-dependent cell-mediated cytotoxicity mechanism. Based on these preclinical data, we treated two patients with HER2-positive SCLC by combination of trastuzumab (6 mg/kg, day 1) and irinotecan (80 mg/m(2), days 1 and 8) every 21 days as the third-line chemotherapy following two prior regimens, first-line carboplatin plus etoposide and second-line amrubicin. One patient achieved partial response after the first cycle and received 6 cycles in total without disease progression for 4.5 months. The other also received 4 cycles and kept stable disease for 3.5 months. This treatment can be continued safely at an outpatient clinic without any severe adverse event. In conclusion, trastuzumab plus irinotecan chemotherapy is promising and feasible against HER2-positive relapsed SCLC. Further clinical studies are encouraged to confirm the antitumor efficacy of trastuzumab in SCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor ErbB-2/metabolismo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Biopsia , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Femenino , Humanos , Inmunohistoquímica , Irinotecán , Neoplasias Pulmonares/diagnóstico , Masculino , Metástasis de la Neoplasia , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Tomografía Computarizada por Rayos X , Trastuzumab , Resultado del TratamientoAsunto(s)
Tos/etiología , Fiebre/etiología , Enfermedades Pulmonares Fúngicas/complicaciones , Micetoma/complicaciones , Scedosporium/aislamiento & purificación , Broncoscopía , Tos/diagnóstico , Diagnóstico Diferencial , Femenino , Fiebre/diagnóstico , Estudios de Seguimiento , Humanos , Enfermedades Pulmonares Fúngicas/diagnóstico , Enfermedades Pulmonares Fúngicas/microbiología , Persona de Mediana Edad , Micetoma/diagnóstico , Micetoma/microbiología , Radiografía Torácica , Tomografía Computarizada por Rayos XRESUMEN
Despite a benign histologic appearance, thymomas have metastatic potential. Here we report a case of a patient with a Masaoka stage IVb thymoma who was successfully treated using a multimodal strategy including systemic chemotherapy, radiofrequency ablation, and thoracic surgery. Despite complete remission after treatment, the patient developed myasthenia gravis with ptosis and neck drop symptoms. Hepatic metastasis of thymoma is a relatively rare occurrence and, to the best of our knowledge, this is the first report about the application of radiofrequency ablation to thymoma.
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Neoplasias Hepáticas , Timoma/tratamiento farmacológico , Timoma/patología , Neoplasias del Timo/tratamiento farmacológico , Neoplasias del Timo/patología , Antineoplásicos/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Biopsia con Aguja , Ablación por Catéter/métodos , Cisplatino/uso terapéutico , Terapia Combinada , Esquema de Medicación , Etopósido/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Persona de Mediana Edad , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/patología , Metástasis de la Neoplasia , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Timectomía , Timoma/clasificación , Timoma/diagnóstico por imagen , Timoma/cirugía , Neoplasias del Timo/clasificación , Neoplasias del Timo/diagnóstico por imagen , Neoplasias del Timo/cirugía , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Theophylline has been used in the management of bronchial asthma and chronic obstructive pulmonary disease for over 50 years. It has not only a bronchodilating effect, but also an anti-inflammatory one conducive to the inhibition of airway remodeling, including subepithelial fibrosis. To date however, whether theophylline has a direct inhibitory effect on airway fibrosis has not been established. To clarify this question, we examined whether theophylline affected the function of lung fibroblasts. Theophylline suppressed TGF-beta-induced type I collagen (COL1) mRNA expression in lung fibroblasts and also inhibited fibroblast proliferation stimulated by FBS and TGF-beta-induced alpha-SMA protein. A cAMP analog also inhibited TGF-beta-induced COL1 mRNA expression in lung fibroblasts. A PKA inhibitor reduced the inhibitory effect of theophylline on TGF-beta-induced COL1 mRNA expression. These results indicate that theophylline exerts anti-fibrotic effects, at least partly, through the cAMP-PKA pathway.
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Fibrosis/patología , Pulmón/citología , Pulmón/efectos de los fármacos , Teofilina/farmacología , Línea Celular , Colágeno Tipo I/genética , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Dexametasona/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis/metabolismo , Expresión Génica/efectos de los fármacos , Humanos , Pulmón/patología , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
The goal of this study was to examine whether IL-6 could directly protect lung resident cells, especially alveolar epithelial cells, from reactive oxygen species (ROS)-induced cell death. ROS induced IL-6 gene expression in organotypic lung slices of wild-type (WT) mice. ROS also induced IL-6 gene expression in mouse primary lung fibroblasts, dose dependently. The organotypic lung slices of WT were more resistant to ROS-induced DNA fragmentation than those of IL-6-deficient (IL-6-/-) mice. WT resistance against ROS was abrogated by treatment with anti-IL-6 antibody. TdT-mediated dUTP nick end labeling stain and electron microscopy revealed that DNA fragmented cells in the IL-6-/- slice included alveolar epithelial cells and endothelial cells. In vitro studies demonstrated that IL-6 reduced ROS-induced A549 alveolar epithelial cell death. Together, these data suggest that IL-6 played an antioxidant role in the lung by protecting lung resident cells, especially alveolar epithelial cells, from ROS-induced cell death.
Asunto(s)
Peróxido de Hidrógeno/farmacología , Interleucina-6/fisiología , Oxidantes/farmacología , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Citoprotección , Fragmentación del ADN/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-6/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Técnicas de Cultivo de Órganos , Estrés Oxidativo , ARN Mensajero/biosíntesis , Especies Reactivas de Oxígeno/farmacologíaRESUMEN
Cigarette smoking is the most crucial factor responsible for chronic obstructive pulmonary disease (COPD). The precise mechanisms of the development of the disease have, however, not been fully understood. Recently, impairment of pulmonary endothelial cells has been increasingly recognized as a critical pathophysiological process in COPD. To verify this hypothesis, we examined how cigarette smoke extract (CSE) damages human umbilical vein endothelial cells (HUVECs). CSE activated c-Jun N-terminal kinase (JNK), and treatment of HUVECs with SP600125, a specific inhibitor of the JNK pathway, significantly suppressed endothelial cell damage by CSE. In contrast, inhibition of the extracellular-regulated kinase or the p38 pathway did not affect the cytotoxicity of CSE. Furthermore, anti-oxidants superoxide dismutase and catalase reduced CSE-induced JNK phosphorylation and endothelial cell injury. These results indicate that CSE damages vascular endothelial cells through the JNK pathway activated, at least partially, by oxidative stress.
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Células Endoteliales/patología , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Quinasas de Proteína Quinasa Activadas por Mitógenos/fisiología , Fumar , Animales , Antracenos/farmacología , Antioxidantes/farmacología , Western Blotting , Catalasa/metabolismo , Células Cultivadas , Daño del ADN , Células Endoteliales/enzimología , Endotelio Vascular/citología , Endotelio Vascular/enzimología , Inhibidores Enzimáticos/farmacología , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , L-Lactato Deshidrogenasa/metabolismo , MAP Quinasa Quinasa 4 , Estrés Oxidativo , Fosforilación , Superóxido Dismutasa/metabolismo , Factores de Tiempo , Venas Umbilicales/citología , Venas Umbilicales/enzimología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The granuloma is a host defence response to persistent pathogenic irritants. In the process of granuloma formation, the activation, migration, and fusion of macrophages occur locally, but the mechanisms involved remain elusive. Tetraspanins regulate cell migration and fusion by organizing functional molecular complexes in membrane microdomains. Here we investigated the role of tetraspanin CD9 in hepatic granuloma formation. Immunostaining of the liver of untreated wild-type mice showed that CD9 was expressed by vascular endothelial cells and perivenular hepatocytes. When intrahepatic granulomas were induced by intravenous injection of Propionibacterium acnes, hepatocyte CD9 was extensively upregulated, while inflammatory cells constituting granulomas were mostly negative for CD9. Compared with wild-type littermates, CD9-knockout mice showed dissemination of Propionibacterium acnes and reduced number and size of granulomas after the injection. Moreover, production of granuloma-inducing cytokines, TNF-alpha and IFN-gamma, was delayed and chemotactic activity for macrophages was suppressed in the liver of mutant mice. These results suggest that CD9 is one of the proteins that promotes granuloma formation in the liver.