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OBJECTIVES: Delayed pneumothorax can cause an emergency room visit and be life-threatening in case of tension pneumothorax after transthoracic needle biopsy. We hypothesized that most delayed pneumothoraces are diagnosed by later enlargement of occult pneumothorax due to the low diagnostic accuracy of a chest X-ray. Lung ultrasound is a highly accurate tool for detection of pneumothorax. The aim of this study is to evaluate the diagnostic accuracy of lung ultrasound for prediction of delayed pneumothorax on chest X-ray. METHODS: This prospective pilot study was performed between April 2020 and July 2020 in Chungnam National University Hospital. The participants underwent chest X-rays and lung ultrasound before, immediately after, and 3 h after transthoracic needle biopsy, respectively. The presence or absence of lung sliding at each anterior BLUE-point on an ultrasound and pneumothorax on a chest X-ray was recorded. RESULTS: Pneumothorax occurred in 17 (35.4%) participants, and three of them underwent chest tube replacement. Of the 17 (35.4%) cases of pneumothorax, five participants (10.4%) were diagnosed with delayed pneumothorax. Three out of five participants showed loss of lung sliding on lung ultrasound before the diagnosis of delayed pneumothorax. Therefore, the sensitivity of lung sliding on lung ultrasound for early detection of delayed pneumothorax was 60%. Two undetected cases were asymptomatic, and the pneumothoraces were exceedingly small and recovered spontaneously. Thus, sensitivity for detection of clinically meaningful delayed pneumothorax requiring chest tube replacement was 100% (2/2). CONCLUSION: Lung ultrasound can probably predict clinically meaningful delayed pneumothorax after transthoracic needle lung biopsy.
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Neumotórax , Biopsia con Aguja/efectos adversos , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Proyectos Piloto , Neumotórax/diagnóstico por imagen , Neumotórax/etiología , Neumotórax/patología , Estudios ProspectivosRESUMEN
BACKGROUND: Despite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR-TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance. METHODS: We used PC9, PC9/GR, and HCC827/GR cell lines to evaluate the activation of autophagy and EGFR-TKI resistance. Chloroquine was applied as an autophagic blocker and verteporfin was utilized as a YAP inhibitor. RESULTS: In this study, we tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR-TKI-resistant lung adenocarcinoma. We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR-TKI-resistant lung adenocarcinoma. Interestingly, we found for the first time that YAP regulates p62 transcription through ERK, and YAP inhibition can suppress the expression of oncogenic p62. We also confirmed that the expressions of p62 and YAP have a positive correlation in EGFR-mutant lung adenocarcinoma patients. To block cell survival via perturbing YAP-p62 axis, we treated EGFR-TKI-resistant lung cancer cells with YAP inhibitor verteporfin. Remarkably, verteporfin effectively caused the death of EGFR-TKI-resistant lung cancer cells by decreasing the expressions of p62 with oncogenic function, YAP, and its target PD-L1. So, the cumulative effect of oncogenic p62 should be considered when using autophagy inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1. CONCLUSION: Finally, we suggest that targeting YAP-p62 signaling axis can be useful to suppress the EGFR-TKI-resistant lung cancer. Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD-L1 at the same time.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Pronóstico , Transducción de Señal , Tasa de Supervivencia , Células Tumorales CultivadasAsunto(s)
COVID-19/epidemiología , Coinfección/epidemiología , Hospitalización/tendencias , Pandemias , SARS-CoV-2 , Centros de Atención Terciaria/estadística & datos numéricos , Anciano , COVID-19/terapia , China/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: The resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Mitogen-inducible gene 6 (Mig-6) is known to inhibit the kinase activity of epidermal growth factor receptor (EGFR). Similarly, numerous studies of mouse models suggested tumor suppressive function of Mig-6 in lung cancer. On the contrary, the results of clinical investigations revealed that lung cancer patients with elevated expression of Mig-6 are associated with a poor prognosis. More recent work showed that unlike wild type (WT) EGFR, mutant EGFR phosphorylates Mig-6 and phosphorylated Mig-6 negatively regulates the degradation of EGFR mutants in lung adenocarcinoma. Here, we tried to untangle the controversies surrounding Mig-6 function as a protagonist or an antagonist of EGFR-TKI resistant lung cancer. METHODS: We compared the expression and phosphorylation status of Mig-6 in the EGFR-TKI resistant lung adenocarcinoma (PC9/GR cells) to EGFR-TKI sensitive lung adenocarcinoma (PC9 cells). We investigated the function of Mig-6 by either depletion or overexpression of Mig-6 in those cells and evaluated the efficacy of combining of Mig-6 knock-down and EGFR-TKI treatment in PC9/GR. The correlation between Mig-6 expressions and the prognoses of lung adenocarcinoma was examined by The Cancer Genome Atlas (TCGA) data and clinical samples. RESULTS: Our results indicated that the expression of Mig-6 was significantly increased in PC9/GR cells compared to that of PC9 cells. The significant portion of Mig-6 existed as a phosphorylated form in PC9 and PC9/GR cells. Moreover, overexpression of Mig-6 significantly increased the cell proliferation, invasion and epithelial mesenchymal transition (EMT) in PC9 cells. Combination of Mig-6 knock-down and EGFR-TKI treatment significantly overcame the EGFR-TKI resistance of PC9/GR cells. In addition, our analyses of clinical samples confirmed that high Mig-6 expressions positively correlate with a poor prognosis and EGFR-TKI resistance in lung adenocarcinoma. CONCLUSION: Our findings reinforce scientific notion of Mig-6 as an oncoprotein in the context of EGFR-TKI resistant lung adenocarcinoma. We propose that targeting Mig-6 may be a promising strategy to overcome the EGFR-TKI resistance in lung cancer.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma del Pulmón/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Anciano , Animales , Línea Celular Tumoral , Conjuntos de Datos como Asunto , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Retroalimentación Fisiológica/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Estimación de Kaplan-Meier , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Ratones , Persona de Mediana Edad , Mutación , Fosforilación/genética , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteolisis/efectos de los fármacos , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genéticaRESUMEN
BACKGROUND: The survival rate of patients with lung cancer has increased significantly over the years, but there has been no further progress in third- or fourth-line therapy. We investigated the efficacy and tolerability of monotherapy with weekly vinorelbine, a semi-synthetic vinca alkaloid, in advanced non-small-cell lung cancer (NSCLC) patients who had previously been treated several times. METHODS: In all, 159 NSCLC patients who received vinorelbine monotherapy as third- or further-line therapy between January 2008 and July 2017 were included in this study. Patients received vinorelbine intravenously at a dose of 25-30 mg/m2/week. RESULTS: Their mean age was 62.4 years. The histologic types of tumor were adenocarcinoma (50.9%), squamous cell carcinoma (42.8%), and others (6.2%). The overall response rate was 19.5% (31/159). The median progression-free survival (PFS) was 3.0 months (95% confidence interval [CI] 2.5-3.5 months), and the median overall survival (OS) after vinorelbine use was 7.6 months (95% CI 6.2-9.0 months). Vinorelbine therapy showed significantly higher efficacy in patients with adenocarcinoma, and these patients had a longer PFS than patients with other types of cancer. Patients who received vinorelbine as fifth- or further-line treatment had a higher response rate and longer PFS and OS than those who received vinorelbine as third- or fourth-line treatment. CONCLUSIONS: Weekly vinorelbine monotherapy may be a feasible therapeutic option for patients with heavily treated, advanced NSCLC, particularly lung adenocarcinoma.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Vinorelbina/uso terapéutico , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Immunotherapy is a new paradigm for the treatment of non-small-cell lung cancer (NSCLC), and targeting the PD-1 or PD-L1 pathway is a promising therapeutic option. Although PD-1/PD-L1 inhibitors are more effective than standard chemotherapy in lung cancer, clinicians are afraid to actively use them because of hyperprogression and pseudoprogression. The aim of this study was to investigate the factors associated with tumor response and serious outcomes. METHODS: We retrospectively collected the medical records of 51 patients with advanced NSCLC who received PD-1/PD-L1 inhibitors between January 2016 and February 2018. RESULTS: The mean patient age was 63.9 years, and 72.5% (37/51) were male. Most (92.2%, 47/51) had received previous systemic treatment. The overall response rate was 21.6% (11/51). The response rate was significantly lower in patients with pleural or pericardial metastasis than in patients without pleural or pericardial metastasis (4.3% vs. 35.7%; P = 0.007). Patients with pleural or pericardial metastasis had a significantly higher rate of adverse events of any grade (91.3% vs. 50.0%; P = 0.002) and grade 3-5 adverse events (52.2% vs. 25.0%; P = 0.046). CONCLUSION: Pleural or pericardial metastasis is a significant factor affecting the efficacy and rate of adverse events in advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. Clinicians should pay attention to the use of immune checkpoint inhibitors in lung cancer patients with pleural or pericardial metastasis.
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Inmunoterapia/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Humanos , Inmunoterapia/métodos , Neoplasias Pulmonares/complicaciones , Persona de Mediana Edad , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: We developed an additional laser guidance system to improve the efficacy and safety of conventional computed tomography (CT)-guided percutaneous transthoracic needle biopsy (PTNB), and we conducted this study to evaluate the efficacy and safety of our system. METHODS: We retrospectively analyzed the medical records of 244 patients who underwent CT-guided PTNB using our additional laser guidance system from July 1, 2015, to January 20, 2016. RESULTS: There were nine false-negative results among the 238 total cases. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of our system for diagnosing malignancy were 94.4% (152/161), 100% (77/77), 100% (152/152), 89.5% (77/86), and 96.2% (229/238), respectively. The results of univariate analysis showed that the risk factors for a false-negative result were male sex (p=0.029), a final diagnosis of malignancy (p=0.033), a lesion in the lower lobe (p=0.035), shorter distance from the skin to the target lesion (p=0.003), and shorter distance from the pleura to the target lesion (p=0.006). The overall complication rate was 30.5% (74/243). Pneumothorax, hemoptysis, and hemothorax occurred in 21.8% (53/243), 9.1% (22/243), and 1.6% (4/243) of cases, respectively. CONCLUSION: The additional laser guidance system might be a highly economical and efficient method to improve the diagnostic efficacy and safety of conventional CT-guided PTNB even if performed by inexperienced pulmonologists.
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OBJECTIVES: Secondhand smoke (SHS) exposure is associated with cardiovascular disease. This study aims to determine the association between SHS exposure estimated by questionnaire and hypertension in Korean never smokers. SETTING: Korean National Health and Nutrition Examination Survey (KNHANES) V was conducted from 2010 to 2012. PARTICIPANTS: We selected the never smokers aged over 20 years who answered the question about the SHS exposure. PRIMARY AND SECONDARY MEASURES: SHS exposure in both the home and work place was estimated using a self-reporting questionnaire. We investigated the association between SHS exposure and hypertension by using multivariate analysis. And we evaluated the mean systolic and diastolic blood pressure values according to SHS exposure after adjusting for possible confounding factors. All analyses were stratified by women and men. RESULTS: There were 10 532 (women 8987 and men 1545) never smokers. We divided the subjects into three groups according to the amount of SHS exposure: none-group I, <2 hour/day-group II and ≥2 hour/day-group III. Using multivariate analysis, hypertension was more commonly associated with group III than group I in women (adjusted OR 1.50, 95% CI 1.00 to 2.04, p=0.011). Adjusted mean systolic and diastolic blood pressure values in women who were not taking antihypertensive medication were significantly elevated in group III by 2.3 and 1.7 mm Hg, respectively. CONCLUSION: SHS exposure is significantly associated with hypertension in women never smokers.
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Exposición a Riesgos Ambientales/efectos adversos , Hipertensión/epidemiología , Hipertensión/etiología , Contaminación por Humo de Tabaco/efectos adversos , Adulto , Estudios Transversales , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Encuestas Nutricionales , República de Corea/epidemiología , Factores de Riesgo , Autoinforme , Factores Sexuales , Factores de TiempoRESUMEN
Developments of EGFR-TKI and immunotherapy targeting the PD1/PD-L1 pathway are considered most important medical breakthroughs in lung cancer treatment. Nowadays, 3rd generation EGFR TKI is widely used for T790M positive 1st and 2nd EGFR-TKI resistant lung cancer patients. Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy resistant patients. It also has changed the concept of conventional anti-cancer therapy in the point of regulating tumor microenvironment. There are many studies linking these two important pathways. Recent studies demonstrated that PD-L1 expression is significantly correlated to the mutation status of EGFR, and activation of EGFR signaling can also induce the expression of PD-L1. However, the real linker between PD-L1 and EGFR signaling remains to be revealed. Our previous study revealed that the Hippo pathway effector YAP confers EGFR-TKI resistance in lung adenocarcinoma, and inhibition of YAP restores sensitivity to EGFR-TKIs. Thus, we examined whether PD-L1 is relevant, in terms of conferring EGFR-TKI resistance and whether YAP directly regulates the expression of PD-L1 in this context. First, we compared the expression levels of PD-L1 and YAP between EGFR-TKI-resistant PC9 cells and the parental PC9 adenocarcinoma cells. The expression levels of both YAP and PD-L1 were markedly higher in the EGFR-TKI-resistant cells compared to the parental cells, suggesting differential expression pattern between two cell types. YAP knockdown significantly decreased the expression of PD-L1 in the EGFR-TKI-resistant cells, while YAP overexpression increased the expression of PD-L1 in the parental PC9 cells. Then, our results revealed that YAP regulates the transcription of PD-L1, and the YAP/TEAD complex binds to the PD-L1 promoter. Surprisingly, knockdown of PD-L1 was sufficient to decrease cell proliferation and wound healing in the EGFR-TKI-resistant PC9 cells. These data suggest a PD1-independent oncogenic function of PD-L1. The Hippo effector YAP plays a crucial role in linking the PD-L1 and EGFR-TKI resistance by directly regulating the expression of PD-L1 in lung cancer. Targeting PD-L1 directly or via YAP could provide an effective therapeutic strategy for EGFR-TKI-resistant lung adenocarcinoma.
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Proteínas Adaptadoras Transductoras de Señales/genética , Antígeno B7-H1/genética , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Fosfoproteínas/genética , ARN Mensajero/genética , Mucosa Respiratoria/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Gefitinib , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/antagonistas & inhibidores , Fosfoproteínas/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/patología , Transducción de Señal , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: The number of pneumonia patients increased suddenly in Korean military hospitals in late December 2014, indicating the urgent need for an epidemic outbreak investigation. METHODS: We conducted a prospective study of pneumonia etiology among immunocompetent young adults admitted to Daejeon Armed Forces hospital. Patient blood and sputum samples were subjected to conventional culture, serology, and polymerase chain reaction tests for respiratory viruses and atypical pathogens. RESULTS: From January to May 2015, we enrolled 191 (189 male) adults with pneumonia; the mean age was 20.1 ± 1.3 years. Five patients had severe pneumonia, and one died. Pathogenic human adenoviruses were most common (HAdV, 153/191 [80.1%]), indicating a HAdV pneumonia outbreak. Genotyping of 35 isolates indicated that 34 matched HAdV-55 and one matched HAdV-2. HAdV pneumonia infected recruit trainees most frequently. High and prolonged fever, nasal congestion, sore throat, and pharyngeal inflammation were significantly more common in the HAdV pneumonia group, compared to patients with other or unknown causes of pneumonia. Only 12% of HAdV pneumonia patients displayed leukocytosis, whereas febrile leukopenia (62.7%) and thrombocytopenia (41%) were commonly observed. HAdV pneumonia patient chest CT scans displayed ground glass opacity (with or without septal thickness) with consolidation in 50.0% of patients. CONCLUSIONS: An outbreak of HAdV respiratory infection occurred at the Korean military training center. HAdV pneumonia exhibited specific laboratory and clinical features, and although most patients were cured without complication, some progressed to respiratory failure and fatality. Therefore, HAdV vaccine should be provided to military trainees in Korea.
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Infecciones por Adenovirus Humanos/epidemiología , Brotes de Enfermedades , Personal Militar , Neumonía Viral/epidemiología , Infecciones por Adenovirus Humanos/complicaciones , Infecciones por Adenovirus Humanos/terapia , Infecciones por Adenovirus Humanos/virología , Adulto , Femenino , Humanos , Masculino , Neumonía Viral/complicaciones , Neumonía Viral/terapia , Neumonía Viral/virología , Estudios Prospectivos , República de Corea/epidemiología , Adulto JovenRESUMEN
Purpose. Topotecan and belotecan are camptothecin derivatives that are used to treat small cell lung cancer (SCLC). This study compared the toxicities and efficacies of belotecan and topotecan monotherapies in patients with SCLC. Methods. We retrospectively reviewed data from 94 patients with SCLC (with or without prior chemotherapy) who were treated using belotecan monotherapy (n = 59, 188 cycles) or topotecan monotherapy (n = 35, 65 cycles) between September 2003 and December 2011. Results. Thrombocytopenia occurred during 42% and 61.5% of the belotecan and topotecan cycles, respectively (p = 0.007). Significant differences between belotecan and topotecan were also observed for grade 4/5 lung infection (3.2% versus 10.8%, resp.; p = 0.003), all-grade headache (3.2% versus 10.8%, resp.; p = 0.017), and grade 4/5 increased liver enzymes (0.5% versus 4.6%, resp.; p = 0.023). The median TTPDs, CSSs, and OSs were 14 months and 11.6 months (p = 0.646), 10 months and 7 months (p = 0.179), and 34.5 months and 21.4 months (p = 0.914) after belotecan and topotecan monotherapy, respectively. Conclusions. Belotecan monotherapy may be safer than topotecan monotherapy in SCLC patients. And in terms of efficacy, belotecan could be comparable to topotecan monotherapy.
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Camptotecina/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Inhibidores de Topoisomerasa I/efectos adversos , Topotecan/efectos adversos , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Camptotecina/efectos adversos , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , República de Corea/epidemiología , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Análisis de SupervivenciaRESUMEN
Somatic mutation in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) is a decisive factor for the therapeutic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma. The stability of mutant EGFR is maintained by various regulators, including heat shock protein 90 (Hsp90). The C terminus of Hsc70-interacting protein (CHIP) is a Hsp70/Hsp90 co-chaperone and exhibits E3 ubiquitin ligase activity. The high-affinity Hsp90-CHIP complex recognizes and selectively regulates their client proteins. CHIP also works with its own E3 ligase activity independently of Hsp70/Hsp90. Here, we investigated the role of CHIP in regulating EGFR in lung adenocarcinoma and also evaluated the specificity of CHIP's effects on mutant EGFR. In HEK 293T cells transfected with either WT EGFR or EGFR mutants, the overexpression of CHIP selectively decreased the expression of certain EGFR mutants (G719S, L747_E749del A750P and L858R) but not WT EGFR. In a pull-down assay, CHIP selectively interacted with EGFR mutants and simultaneously induced their ubiquitination and proteasomal degradation. The expressions of mutant EGFR in PC9 and H1975 were diminished by CHIP, while the expression of WT EGFR in A549 was nearly not affected. In addition, CHIP overexpression inhibited cell proliferation and xenograft's tumor growth of EGFR mutant cell lines, but not WT EGFR cell lines. EGFR mutant specific ubiquitination by CHIP may provide a crucial regulating mechanism for EGFR in lung adenocarcinoma. Our results suggest that CHIP can be novel therapeutic target for overcoming the EGFR TKI resistance.
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Adenocarcinoma/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Células A549 , Adenocarcinoma/genética , Adenocarcinoma/patología , Animales , Western Blotting , Línea Celular Tumoral , Proliferación Celular/genética , Receptores ErbB/genética , Femenino , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Unión Proteica , Proteolisis , Trasplante Heterólogo , Carga Tumoral/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Spontaneous regression of malignant tumors is rare especially of lung tumor and biological mechanism of such remission has not been addressed. We report the case of a 79-year-old Korean patient with non-small cell lung cancer, squamous cell cancer with a right hilar tumor and multiple lymph nodes, lung to lung metastasis that spontaneously regressed without any therapies. He has sustained partial remission state for one year and eight months after the first histological diagnosis.
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The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is significantly limited by various resistance mechanisms to those drugs. The resistance to EGFR-TKI is largely divided by two classes; acquired resistance after EGFR-TKI treatment, and primary resistance marked by cancer cell's dependence on other oncogene, such as KRAS. YAP has emerged as critical oncogene in conferring drug resistance against targeted therapy. In this study, we evaluated the role of YAP in primary and acquired EGFR-TKI resistance using gefitinib-resistant A549 and PC9 cells and their parental cell lines. Our study revealed that EGFR-TKI resistance is associated with enhanced YAP activity. Notably, YAP activation was independent of the Hippo pathway. We confirmed that AXL is a downstream target of YAP that confers EGFR-TKI resistance. And our results showed that YAP can induce ERK activation in lung adenocarcinoma. The combination of YAP inhibition with EGFR-TKI overcomes primary and acquired EGFR-TKI resistance. We also found increased YAP expression in human lung cancer after acquiring EGFR-TKI resistance. Collectively, we suggest a novel EGFR-TKI resistance mechanism involving YAP activation and suggest targeting YAP and EGFR simultaneously may be a breakthrough treatment of primary and acquired EGFR-TKI resistant lung cancer.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Fosfoproteínas/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Células A549 , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Factor de Crecimiento Epidérmico/administración & dosificación , Vía de Señalización Hippo , Humanos , Fosfoproteínas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción , Resultado del Tratamiento , Proteínas Señalizadoras YAPRESUMEN
Spontaneous regression (SR) of cancer is defined as a complete or partial, temporary or permanent disappearance of all or at least some relevant parameters of malignant disease with inadequate or no treatment. SR of cancer is an extremely rare phenomenon. We report a case of a 67-year-old man who experienced SR of non-small-cell lung cancer (NSCLC), which progressed after fifth-line chemotherapy and regressed after chemotherapy ceased. Surprisingly, the primary tumor size continued to decrease for more than 13 months and his general condition markedly improved after discontinuation of the chemotherapy. To our knowledge, this is the first report of SR in a patient with NSCLC that was not responsive to a fifth round of chemotherapy.
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BACKGROUND: The efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy can be measured based on the rate of treatment response, based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria or progression-free survival (PFS). However, there are some patients harboring sensitive EGFR mutations who responded poorly to EGFR-TKI therapy. In addition, there is variability in the PFS after EGFR-TKI treatment. METHODS: We performed a retrospective analysis of the medical records of 85 patients with non-small cell lung cancer, who had achieved a stable disease or better response at the first evaluation of treatment response, after receiving a 2-month course of gefitinib. We calculated the tumor shrinkage rate (TSR) by measuring the longest and perpendicular diameter of the main mass on computed tomography before, and 2 months after, gefitinib therapy. RESULTS: There was a significant positive correlation between the TSR and PFS (R=0.373, p=0.010). In addition, a simple linear regression analysis showed that the TSR might be an indicator for the PFS (B±standard error, 244.54±66.79; p=0.001). On univariate analysis, the sex, histologic type, smoking history and the number of prior chemotherapy regimens, were significant prognostic factors. On multivariate regression analysis, both the TSR (ß=0.257, p=0.029) and adenocarcinoma (ß=0.323, p=0.005) were independent prognostic factors for PFS. CONCLUSION: Our results showed that the TSR might be an early prognostic indicator for PFS in patients receiving EGFR-TKI therapy.
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Third and fourth line chemotherapy agents are not helpful in the setting of extensive stage small cell lung cancer (SCLC). We describe the case of a 43-year-old Korean patient with T4N3M1b extensive stage SCLC who responded remarkably well to treatment and experienced a prolonged progression-free survival (PFS) period following treatment with fourth line ifosfamide and carboplatin after experiencing disease progression with three previous regimens. Additionally, third line cyclophosphamide, doxorubicin (Adriamycin), and vincristine demonstrated long-term PFS periods.
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BACKGROUND: Although exposure to second-hand smoke (SHS) has been associated with various medical conditions, only limited data are available on its association with health-related quality of life (HRQOL), particularly data obtained with the EQ-5D or EQ visual analogue scale (VAS). METHODS: This cross-sectional study evaluated 10,532 adult never-smokers who participated in the fifth Korea National Health and Nutrition Examination Survey. By using linear regression models to adjust for possible confounders and incorporating survey weights in analyses, the association between exposure to SHS and HRQOL-measured with the EQ-5D index and the EQ-VAS score-was evaluated. Data were further stratified by the amount of exposure time. RESULTS: After weighted analysis and adjustment, exposure to SHS was significantly associated with lower measures on the EQ-5D index (ß = -0.007, P = 0.005) and EQ-VAS score (ß = -1.936, P < 0.001). When comparing the unexposed group with the groups exposed <2h/day and ≥2h/day, exposure to a longer duration of SHS was significantly associated with lower scores on the EQ-5D index and the EQ-VAS score. CONCLUSION: In conclusion, exposure to SHS was associated with reduced HRQOL measured by the EQ-5D index and EQ-VAS score, revealing a dose-response relationship.