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BACKGROUND: Lymphovascular invasion (LVI), which includes vascular or lymphatic invasions, is a representative prognostic factor even in patients with resected stage IA non-small cell lung cancer (NSCLC). Because tegafur-uracil is effective on cancers with LVI, we conducted a multi-center single-arm phase II study to estimate the efficacy of adjuvant tegafur-uracil in patients with LVI-positive stage IA NSCLC. METHODS: Patients with completely resected LVI-positive stage IA NSCLC were registered. LVI was diagnosed by consensus of two of three pathologists. Adjuvant chemotherapy consisted of 2 years of oral tegafur-uracil at 250 mg/m2/day. Fifty-five patients from 7 institutions were enrolled from June 2007 to September 2012. RESULTS: Among the 52 eligible patients, 36 (69.2%) completed the treatment course. There were 39 male and 13 female patients. The observation period was calculated as 562 to 3107 days using the reverse Kaplan-Meier method. The 5-year overall and relapse free survival rates were 94.2 and 88.5% respectively, which were significantly better than that of any other studies conducted on patients with LVI-positive stage IA NSCLC. Notably, the overall survival rate was 15% better than that of our prior retrospective study. The retrospective analysis of stage IA NSCLC patients who had received an operation in the same period revealed that the 5-year overall survival rate of the LVI positive group was 73.6% when adjuvant chemotherapy was not applied. Among 55 safety analysis sets, 4 cases of grade 3 hepatic function disorder (9.1%) and 5 cases of grade 2 anorexia (10.9%) were most frequently observed. No grade 4 adverse effects were encountered. CONCLUSION: A 2-year course of oral tegafur-uracil administration is feasible and might have a significant benefit in the adjuvant treatment of LVI-positive stage IA NSCLC. TRIAL REGISTRATION: UMIN identifier: UMIN000005921 ; Date of enrolment of the first participant to the trial: 19 June 2007; Date of registration: 5 July 2011 (retrospectively registered).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vasos Sanguíneos/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Vasos Linfáticos/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Quimioterapia Adyuvante/efectos adversos , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Neutropenia/inducido químicamente , Cooperación del Paciente , Neumonectomía , Profármacos/administración & dosificación , Profármacos/efectos adversos , Estudios Prospectivos , Tegafur/administración & dosificación , Tegafur/efectos adversos , Uracilo/administración & dosificación , Uracilo/efectos adversosRESUMEN
INTRODUCTION: IgG4-related disease is characterized by IgG4-positive plasmacyte infiltration into various organs, but its etiology is not unknown. OBJECTIVES: To elucidate the etiology of IgG4-related disease. METHODS: We experienced an interesting case of IgG4-related lung disease complicated by chronic EB virus infection. RESULTS: A 70-year-old male visited our hospital due to failure of pneumonia treatment. Chest computed tomography (CT) showed consolidation in the right middle field and slight mediastinal lymphadenopathy in the subcarinal region. Lung consolidation improved with antibiotics; subcarinal lymphadenopathy progressed after 4 months. Malignant lymphoma was suspected given elevated sIL2-R levels (1862 U/mL). Patchy ground glass opacities appeared in the bilateral lung field just before surgical biopsy. He was diagnosed with IgG4-related lung disease after inspection of a pathological specimen obtained from the right upper lung and right hilar lymph node. EB virus-infected cells were also detected in the lymph node. Blood examination revealed EB virus viremia, but the patient did not present with symptoms or organ involvement. This led to a diagnosis of asymptomatic chronic EB virus infection. CONCLUSION: Recent studies have suggested an association between EB virus infection and IgG4-related diseases in the pathological exploration of surgically resected lymph nodes. Our case is the first case of IgG4-related lung disease in which EB virus infection was both pathologically and clinically proved. The present case is of particular interest in view of this newly reported association, and may serve as a fundamental report for future studies connecting EB virus infection with IgG4-related diseases.
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Infecciones por Virus de Epstein-Barr/complicaciones , Inmunoglobulina G/sangre , Enfermedades Pulmonares/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Ganglios Linfáticos/patología , Neumonía/complicaciones , Anciano , Antiinflamatorios/uso terapéutico , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Pulmón/inmunología , Pulmón/patología , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/patología , Ganglios Linfáticos/virología , Masculino , Neumonía/diagnóstico , Neumonía/tratamiento farmacológico , Prednisolona/administración & dosificación , Prednisolona/uso terapéutico , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
A 70-year-old man presented to our hospital because of difficulty with discrete movement of the right upper limb and dysarthria. Computed tomography(CT)of the head revealed a chronic subdural hematoma(CSDH)on the left side. The patient underwent single burr-hole irrigation and drainage on the same day. In addition to the burr hole, a cross-shaped dural incision was made which revealed a thick outer membrane and solidified hematoma. We removed as much of the clotted hematoma as possible using a curved suction tube under neuroendoscopy. The postoperative CT revealed that the hematoma was partially removed and the mass effect was reduced. As a result, the patient's neurological deficits improved. We reached a diagnosis of organizing CSDH following histologic examination of the removed hematoma that showed inflammatory cell infiltration and multiplication of fibroblasts. Neuroendoscopic hematoma evacuation via a burr hole is minimally invasive and may be a useful procedure in the treatment of some cases of organizing CSDH.
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Legrado , Hematoma Subdural Crónico/cirugía , Neuroendoscopía , Succión , Anciano , Craneotomía/métodos , Legrado/métodos , Hematoma Subdural Crónico/diagnóstico , Hematoma Subdural Crónico/patología , Humanos , Masculino , Succión/métodos , Resultado del TratamientoRESUMEN
AIMS: To investigate the histological evolution in the development of pleuroparenchymal fibroelastosis (PPFE). METHODS AND RESULTS: We examined four patients who had undergone surgical lung biopsy twice, or who had undergone surgical lung biopsy and had been autopsied, and in whom the histological diagnosis of the first biopsy was not PPFE, but the diagnosis of the second biopsy or of the autopsy was PPFE. The histological patterns of the first biopsy were cellular and fibrotic interstitial pneumonia, cellular interstitial pneumonia (CIP) with organizing pneumonia, CIP with granulomas and acute lung injury in cases 1, 2, 3, and 4, respectively. Septal elastosis was already present in the non-specific interstitial pneumonia-like histology of case 1, but a few additional years were necessary to reach consolidated subpleural fibroelastosis. In case 3, subpleural fibroelastosis was already present in the first biopsy, but only to a small extent. Twelve years later, it was replaced by a long band of fibroelastosis. The septal inflammation and fibrosis and airspace organization observed in the first biopsies were replaced by less cellular subpleural fibroelastosis within 3-12 years. CONCLUSIONS: Interstitial inflammation or acute lung injury may be an initial step in the development of PPFE.
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Enfermedades Pulmonares Intersticiales/patología , Pulmón/patología , Fibrosis Pulmonar/patología , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We herein report a case involving a 58-year-old female patient with multiple cystic lesions in the right lobe of the lung. The lesions were revealed on chest computed tomography in 2002 and followed up. Transbronchial lung biopsy showed no malignancy in June 2013. The lesions gradually increased in size and thickness and were associated with fluid-filled cysts. We performed a right lower lobectomy in November 2013. Pathological examination revealed inflammatory pseudotumor. Such a case of inflammatory pseudotumor presenting as a pulmonary cyst has not been previously described. Intractable infection and inflammation are regarded as common causes of inflammatory pseudotumor. This condition should be considered in patients with a medical history consistent with infectious disease and a pulmonary cyst found on chest computed tomography.
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Quistes/cirugía , Enfermedades Pulmonares/cirugía , Granuloma de Células Plasmáticas del Pulmón/cirugía , Neumonectomía , Biopsia , Quistes/diagnóstico por imagen , Quistes/etiología , Quistes/patología , Femenino , Humanos , Inflamación/complicaciones , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/patología , Persona de Mediana Edad , Granuloma de Células Plasmáticas del Pulmón/diagnóstico por imagen , Granuloma de Células Plasmáticas del Pulmón/etiología , Granuloma de Células Plasmáticas del Pulmón/patología , Radiografía Torácica , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVES: 3D turbo field echo with diffusion-sensitised driven-equilibrium preparation (DSDE-TFE) is a novel non-echo planar technique for diffusion-weighted (DW) imaging. The purpose of this study was to differentiate intraorbital lymphoma from immunoglobulin G4-related disease (IgG4-RD) using the apparent diffusion coefficient (ADC) derived from DSDE-TFE. METHODS: Fifteen patients with lymphomas and 8 with IgG4-RDs underwent imaging. ADC and signal intensities compared with normal grey matter on T1-weighted images, fat-suppressed T2-weighted images and fat-suppressed postcontrast T1-weighted images were measured. Statistical analyses were performed using the Mann-Whitney U test and receiver operating characteristic (ROC) analysis. RESULTS: Intraorbital lesions were clearly visualised on DSDE-TFE without obvious geometrical distortion. The ADC of lymphoma (1.25 ± 0.50 × 10(-3) mm(2)/s; mean ± standard deviation) was significantly lower than that of IgG4-RD (1.67 ± 0.84 × 10(-3) mm(2)/s; P < 0.05). Conventional sequences could not separate lymphoma from IgG4-RD (0.93 ± 0.18 vs. 0.94 ± 0.21 on T1-weighted images, 0.92 ± 0.17 vs. 0.95 ± 0.14 on T2-weighted images and 2.03 ± 0.35 vs. 2.30 ± 0.58 on postcontrast T1-weighted images, for lymphoma and IgG4-RD, respectively; P > 0.05). ROC analysis showed the best diagnostic performance with ADC. CONCLUSION: The apparent diffusion coefficient derived from diffusion-sensitised driven-equilibrium preparation techniques may help to differentiate lymphoma from immunoglobulin G4-related disease. KEY POINTS: ⢠Distinguishing between orbital lymphoma and immunoglobulin G4-related disease can be difficult ⢠Intraorbital lesions were clearly visualised on diffusion-sensitised driven-equilibrium preparation magnetic resonance techniques. ⢠Variations in field homogeneity do not affect DSDE-TFE techniques all that much. ⢠ADCs derived from DSDE-TFE may help differentiate lymphoma from IgG4-RD.
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Enfermedades Autoinmunes/patología , Imagen de Difusión por Resonancia Magnética/métodos , Inmunoglobulina G/metabolismo , Linfoma/patología , Neoplasias Orbitales/patología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Linfoma/diagnóstico , Masculino , Persona de Mediana Edad , Órbita/patología , Neoplasias Orbitales/diagnóstico , Curva ROC , Estudios Retrospectivos , Estadísticas no ParamétricasRESUMEN
PICT1 is a key regulator of the MDM2-TP53 pathway. High mRNA expression levels of PICT1 are associated with poor prognosis in several cancers with wild-type TP53. In this study, we identified the PICT1 protein expression profile in non-small cell lung cancer (NSCLC) with wild-type TP53 in the nucleolus and cytoplasm, and revealed the relationship between PICT1 expression and patient clinicopathological factors. PICT1 expression in the tumor cells of 96 NSCLC patients with wild-type TP53 was evaluated by immunohistochemistry. Forty-three of 96 (44.8%) NSCLC samples were positive for nucleolar PICT1, while 40/96 (41.7%) NSCLC samples were positive for cytoplasmic PICT1. There was no correlation between nucleolar PICT1 expression and clinicopathological factors. However, cytoplasmic PICT1 expression was significantly correlated with sex, smoking history, differentiation, lymphatic invasion and pathological stage. In multivariate analysis, lymphatic invasion was significantly associated with cytoplasmic PICT1 expression (hazard ratio: 5.02, P = 0.026). We scrutinized PICT1 expression in samples of NSCLC with wild-type TP53, and showed a correlation between cytoplasmic PICT1 expression and several clinicopathological factors in these patients. Our results indicate that cytoplasmic PICT1 expression is a poor prognostic factor and is associated with tumor progression via lymphatic invasion in these patients.
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BACKGROUND: The clinical significance of Brachyury expression and its relationship to epithelial-mesenchymal transition in primary lung carcinoma is unclear. METHODS: Expression of Brachyury mRNA was investigated in 104 surgically resected primary lung carcinoma tissues. Immunohistochemical analysis of Brachyury transcription factor, Slug, E-cadherin, IL-8, N-cadherin, and Ki67 was performed in 67 of 104 cases, and their expression was correlated to prognoses and clinicopathological factors. RESULTS: Brachyury mRNA expression in primary lung carcinoma tissues was a significant predictor of poor prognosis for 5-year disease-free survival and overall survival rates and was significantly correlated to vascular invasion, lymphatic permeation, histological grade, pathologic T stage, and pathologic N stage (P < 0.05). Brachyury mRNA expression was significantly inversely correlated to E-cadherin expression (P = 0.0252) and positively correlated to IL-8 protein (P = 0.0241) and to Slug protein (P = 0.0243) in adenocarcinoma tissues. CONCLUSIONS: A positive association between Brachyury and Slug and IL-8, and a negative association with E-cadherin may lead to invasiveness and metastasis in primary lung carcinoma. Brachyury mRNA expression is a significant predictor of poor prognosis in primary lung carcinoma.
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Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Transición Epitelial-Mesenquimal , Proteínas Fetales/genética , Neoplasias Pulmonares/genética , Proteínas de Dominio T Box/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Femenino , Proteínas Fetales/metabolismo , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas de Dominio T Box/metabolismoRESUMEN
Excluding epidermal growth factor receptor (EGFR) mutation, v-Ki-ras2/Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion, the genetic alterations involved in lung adenocarcinogenesis, especially those linked to poor clinical outcomes, are still unknown. In this study, we analyzed abnormal checkpoint gene with forkhead-associated domain and ring finger (CHFR) methylation along with the above 3 mutations in 165 lung adenocarcinomas, evaluated the spectrum of each molecular abnormality, and correlated the results with clinical and pathologic variables. Reverse transcription-polymerase chain reaction assay, reverse transcription-polymerase chain reaction followed by direct DNA sequencing, and methylation-specific polymerase chain reaction were performed to detect these 3 mutations and CHFR hypermethylation. The EML4-ALK transcript or CHFR hypermethylation was found in 11 (6.7%) or 16 (10%) adenocarcinomas, respectively, whereas EGFR or KRAS mutation was detected in 48 (29%) or 13 (8%) cases, respectively. EGFR mutations occurred in patients who were negative for both CHFR hypermethylation and KRAS mutation. Among the 4 genetic or epigenetic abnormalities, only CHFR hypermethylation was significantly correlated with poor prognosis and lymphatic vessel invasion (P = .024). Histopathologically, the molecular abnormality that correlated with alveolar-destructive growth was the CHFR hypermethylation rather than the EGFR mutation (P = .03). Our results demonstrate that CHFR hypermethylation maybe one of the molecular abnormalities involved in a subset of lung adenocarcinomas with poor prognoses that might be induced by destructive growth and lymphatic vessel invasion of carcinoma cells. Thus, CHFR abnormality might be pursued as a novel therapeutic target against lung adenocarcinoma without an already-known mutation.
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Adenocarcinoma/genética , Proteínas de Ciclo Celular/genética , Metilación de ADN , Silenciador del Gen , Neoplasias Pulmonares/genética , Mutación , Proteínas de Neoplasias/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Anciano , Análisis Mutacional de ADN , ADN de Neoplasias/análisis , Femenino , Humanos , Japón/epidemiología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Estadificación de Neoplasias , Proteínas de Unión a Poli-ADP-Ribosa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ubiquitina-Proteína LigasasRESUMEN
Aurora-B is a key regulator of mitosis, and the overexpression has been detected in a variety of solid tumors. The Aurora-B overexpression has been suggested to correlate with clinical aggressiveness and aneuploidy in vitro, however, the frequency of overexpression of Aurora-B protein, the association with clinicopathologic parameters and aneuploidy remain poorly defined in non-small-cell lung cancer (NSCLC). Using 157 surgical specimens of human NSCLC, we here show that overexpression of Aurora-B proteins are significantly correlated with aneuploidy and poor outcomes in NSCLC. We examined immunohistochemical protein expression of Aurora-B, and DNA ploidy by laser scanning cytometry in 157 NSCLC cases. Aurora-B overexpression was found in 83 cases (53%) of NSCLC, and was significantly correlated with vascular invasion (p=0.012), poor differentiation (p<0.001), larger tumor size (p=0.010) and lymph node metastasis (p=0.05) and poor prognosis (p=0.011). Aneuploidy was found in 87 cases (57%), and was significantly correlated with Aurora-B overexpression (p=0.0065). Logistic multivariate analysis revealed overexpression of Aurora-B protein to be significant risk factors for aneuploidy compared with other factors. These results indicate that Aurora-B overexpression may contribute to malignant potential and increased aneuploidy in NSCLC. Thus, Aurora-B may serve as a new therapeutic target in against patients with NSCLC, although further studies will be necessary.
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Aneuploidia , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Aurora Quinasa B , Aurora Quinasas , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/genética , Femenino , Humanos , Inmunohistoquímica , Citometría de Barrido por Láser , Modelos Logísticos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Ploidias , Pronóstico , Factores de Riesgo , Carga TumoralRESUMEN
In contrast to other internal organs, pulmonary arterial hypoperfusion does not always show ischemic changes in the lung parenchyma. Pulmonary thromboembolism (PTE)-related lung injury is extremely rare except in the case of pulmonary infarctions, in which PTE occasionally causes necrosis of the parenchyma. We describe the case of an 86-year-old woman who presented with respiratory failure and bilateral ground-glass opacity predominantly the upper lobes. Autopsy revealed a saddle-shaped old organized thrombi in the main pulmonary artery, relatively fresh thrombi in both pulmonary arteries, and localized diffuse alveolar damage (DAD) in the bilateral upper lung fields. The hypoperfused regions resulting from the thromboembolism anatomically coincided with the pulmonary lesion where DAD was identified. Although PTE is not regarded as a causal factor of DAD, it might induce DAD as a result of hypoperfusion in limited cases.
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Genistein, a major soy isoflavone having weak estrogenic activities, has been suggested to reduce the risk of breast cancer incidence. However, many studies have yielded inconsistent results. We investigated the effects of dietary genistein on the development of breast cancer using ethyl methanesulphonate (EMS) chemically induced rat model of hormone-dependent mammary carcinoma. Female Wistar King A rats were orally given EMS for 12 wk and fed isoflavone-free NIH-07PLD diets with or without genistein, beginning immediately after weaning period. All EMS-treated rats fed either diet developed estrogen and/or progesterone receptor-positive mammary carcinoma by 24 wk. The addition of either low or high genistein, which produced the plasma concentrations comparable with those observed in humans consuming high soy diets, did not show any preventive activity. Soy-containing pellet food, exhibiting substantial plasma concentrations of isoflavones such as genistein, daidzein, equol, and glycitein, significantly increased the latency periods, compared to either NIH-07PLD diet with low (P = 0.027) or high (P = 0.034) genistein. Body weights, total EMS uptakes, and urinary estradiol concentrations were not significantly different among groups. These data indicate that genistein does not exert clear preventive effects and that isoflavone components other than genistein might be preventive against hormone-dependent mammary carcinogenesis.
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Dieta , Metanosulfonato de Etilo , Genisteína/administración & dosificación , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/prevención & control , Animales , Estradiol/orina , Femenino , Genisteína/sangre , Isoflavonas/sangre , Neoplasias Mamarias Experimentales/química , Ratas , Ratas Wistar , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Alimentos de SojaRESUMEN
A 26-year-old man with unresectable inflammatory myofibroblastic tumor (IMT) presented with multiple metastases in the thoracic vertebra and lymph nodes as detected by positron emission tomography (PET) received chemotherapy with carboplatin plus paclitaxel. After three cycles of chemotherapy, fluorine-18-fluorodeoxyglucose (FDG)-PET/CT revealed tumor regression and significant reduction of FDG uptake in all lesions. The patient received six cycles of chemotherapy without any severe adverse event, and there was no sign of disease progression for seven months. This regimen is well tolerated and may be considered the treatment of choice for unresectable IMT.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Neoplasias del Mediastino/tratamiento farmacológico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Paclitaxel/uso terapéutico , Adulto , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Fluorodesoxiglucosa F18 , Humanos , Metástasis Linfática/diagnóstico por imagen , Masculino , Neoplasias del Mediastino/diagnóstico por imagen , Neoplasias del Mediastino/patología , Estadificación de Neoplasias , Neoplasias de Tejido Muscular/diagnóstico por imagen , Neoplasias de Tejido Muscular/secundario , Tomografía de Emisión de Positrones , Radiografía , Vértebras Torácicas/diagnóstico por imagen , Resultado del TratamientoRESUMEN
High expression levels of TrkB and BDNF are associated with aggressive malignant behavior in tumor cells and a poor prognosis in patients with various types of cancer. In this study, we aimed to identify the relationship between TrkB and BDNF expression and clinicopathological variables and prognosis in non-small cell lung cancer (NSCLC). We evaluated TrkB and BDNF expression in the tumor cells of 102 NSCLC patients by immunohistochemistry. Out of all clinicopathological factors examined, only vascular invasion was significantly correlated with TrkB (P=0.010) and BDNF (P=0.015) expression. TrkB-positive tumors had significantly worse disease-free survival (P=0.0094) and overall survival (P=0.0019) than TrkB-negative tumors, and TrkB expression was an independent prognostic factor for disease-free survival (HR 3.735, 95% CI 1.560-11.068, P=0.002) and overall survival (HR 4.335, 95% CI 1.534-15.963, P=0.004) in multivariate analysis. Finally, our analysis revealed that co-expression of TrkB and BDNF conferred poorer prognosis compared with overexpression of either protein alone. Our results indicate that expression of TrkB and BDNF is associated with poor prognosis in NSCLC patients.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Receptor trkB/metabolismo , Anciano , Factor Neurotrófico Derivado del Encéfalo/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Expresión Génica , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Receptor trkB/genéticaRESUMEN
We herein describe an asymptomatic 31-year-old male who was admitted for an investigation of an abnormal pleural tumor detected by chest radiography. We performed various preoperative investigations including fluorodeoxyglucose-positron emission tomography. The maximum standardized uptake value (SUVmax) was 2.2, and malignancy could not be ruled out. We therefore carried out a thoracoscopy-assisted partial resection of the right upper lobe combined with a parietal pleurectomy. The pathological examination showed that there was a tumor localized with pleural amyloidosis.
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Amiloidosis/diagnóstico , Enfermedades Pleurales/diagnóstico , Adulto , Amiloidosis/patología , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Imagen por Resonancia Magnética , Masculino , Enfermedades Pleurales/patología , Tomografía de Emisión de Positrones , Intensificación de Imagen Radiográfica , Radiografía TorácicaRESUMEN
PURPOSE: TrkB has been involved in poor cancer outcome. TrkB mutations have been reported in non-small cell lung cancer. In this study, we aimed at characterizing the role of three potentially sensitizing TrkB mutations previously reported in lung cancer. EXPERIMENTAL DESIGN: We characterized three activation loop mutants of TrkB (M713I, R715G, and R734C) in terms of pathway activation/phosphorylation, migration, anchorage-independent growth, and sensitivity to a Trk inhibitor, using NIH3T3 cells and Baf3 cells. We also sequenced the tyrosine kinase domain of TrkB in a large number of lung cancer samples of East-Asian origin and cell lines. RESULTS: None of the mutants were constitutively active in NIH3T3 transformation and migration assays. M713I and R734C mutants showed low levels of autophosphorylation in comparison with wild-type TrkB. Although R715G showed similar level of autophosphorylation to wild-type TrkB on brain-derived neurotrophic factor stimulation, the mutant was not as competent as wild-type TrkB in supporting interleukin-3-independent growth of Baf3 cells. In addition, the Trk inhibitor AZD6918 inhibited wild-type TrkB-induced cell migration and cell growth, whereas the mutants were relatively resistant to the Trk inhibitor compared with wild-type TrkB. We could not confirm the presence of nonsynonymous mutation in 78 lung cancer samples and 29 cell lines. CONCLUSIONS: Wild-type, but not mutant, TrkB enhances cell migration and transformation. Our study suggests that TrkB mutations should not be used for selection of patients with lung cancer treated with Trk inhibitors. High expression of wild-type TrkB might be beneficial for studies of Trk inhibitors.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Mutación , Receptor trkB/genética , Secuencia de Aminoácidos , Animales , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Análisis Mutacional de ADN , Regulación Enzimológica de la Expresión Génica/fisiología , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Neoplasias Pulmonares/patología , Ratones , Modelos Biológicos , Datos de Secuencia Molecular , Mutación/fisiología , Células 3T3 NIH , Receptor trkB/fisiología , Homología de Secuencia de Aminoácido , Células Tumorales CultivadasRESUMEN
Podoplanin is expressed in a variety of malignant cells, and is generally regarded as a factor promoting tumor progression in conventional studies. Conversely, a recent clinicopathological study has revealed that low podoplanin in cancer cells was correlated with poor prognosis of patients with stage IB lung squamous cell carcinoma (LSCC). We here evaluated the clinicopathological relationship between cancer-cell podoplanin expression and clinicopathological parameters in 40 cases of LSCC (stage I-III). Immunohistochemical podoplanin expression significantly correlated with N classification and pathological stage, but not with other clinicopathological parameters. Notably, all 16 cases with high podoplanin expression unexceptionally exhibited pathological N0 status. Cases without nodal metastasis showed a significantly higher podoplanin-positive score. Furthermore, patients with high podoplanin expression exhibited a significantly longer survival time and disease-free time. These findings suggest that immunohistochemical analysis for podoplanin may serve as a marker of risk of nodal metastasis and prognosis in patients with LSCC.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/química , Neoplasias Pulmonares/química , Glicoproteínas de Membrana/análisis , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/secundario , Distribución de Chi-Cuadrado , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Aberrant promoter methylation of the checkpoint gene with forkhead-associated domain and ring finger (CHFR) gene is frequently detected in human cancer. We previously demonstrated that diminished CHFR expression was significantly correlated with both poor prognosis and heavy smoking in nonsmall cell lung cancer (NSCLC). Conversely, epidermal growth receptor (EGFR) mutation is detected in NSCLC among those who have never smoked or smoked lightly. To address the frequency of CHFR hypermethylation as well as differences in the distributions and clinicopathologic backgrounds against EGFR mutation in NSCLC, we investigated a large group of 208 NSCLC patients, including 165 with adenocarcinoma (ADC), 40 with squamous cell carcinoma and three others. We found that CHFR hypermethylation and EGFR mutation are mutually exclusive and have contrastive clinicopathologic backgrounds in NSCLC. Methylation-specific polymerase chain reaction (MSP) and direct DNA sequencing were performed to detect CHFR hypermethylation and EGFR mutation, respectively. CHFR hypermethylation was found in 29 cases (14%) (16 ADC (8%), 12 SCC (6%) and one adenosquamous carcinoma), while EGFR mutation was detected in 48 (23%) cases, all of which were ADC. CHFR hypermethylation and EGFR mutation were mutually exclusive (p = 0.004). NSCLC with altered CHFR was significantly correlated with smoking history, poor differentiation, lymphatic invasion, and poor prognosis; this contrasted sharply with EGFR mutation, which had statistically better clinical outcomes. Our results demonstrate that CHFR loss might be critical for the tumorigenesis of NSCLC in patients with a history of smoking and induces tumors of a more malignant phenotype than the EGFR mutation. Thus, CHFR alteration should be considered a therapeutic target against NSCLC in patients with poor prognoses.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas de Ciclo Celular/genética , Metilación de ADN , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutación , Proteínas de Neoplasias/genética , Anciano , Carcinoma de Pulmón de Células no Pequeñas/terapia , Proteínas de Ciclo Celular/metabolismo , Femenino , Genes ras , Humanos , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa , Resultado del Tratamiento , Ubiquitina-Proteína LigasasRESUMEN
Experiments using cancer cell lines have revealed that CHFR methylation correlates with sensitivity to microtubule inhibitors. However, this marker may not benefit actual clinical cases because it is difficult to detect CHFR methylation without surgically resected samples. Thus, a more easily accessible marker that correlates with sensitivity to microtubule inhibitors might be useful in NSCLC, especially in advanced cases. In this study, we show that EGFR gene status and smoking are predict the efficacy of treatment with microtubule inhibitors in NSCLC. Chemosensitivity to paclitaxel and six other chemotherapeutic agents was evaluated using the succinate dehydrogenase inhibition (SDI) method in 69 NSCLC cases, consisting of 48 adenocarcinomas, 20 squamous cell carcinomas and 1 large cell carcinoma. Next, we evaluated the relationships between CHFR or EGFR status and clinicopathologic data. Methylation-specific PCR (MSP) and direct DNA sequencing were performed to detect aberrant methylation of CHFR and EGFR mutations, respectively. CHFR gene promoter methylation and EGFR gene mutation were observed in 11 cases (15.9%) and 7 cases (10.1%), respectively. The SDI method revealed that CHFR gene methylation was significantly related to high sensitivity to paclitaxel (p.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas de Ciclo Celular/genética , Genes erbB-1 , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de Neoplasias/genética , Paclitaxel/uso terapéutico , Fumar , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Metilación de ADN , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mutación , Proteínas de Neoplasias/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , Análisis de Secuencia de ADN , Succinato Deshidrogenasa/antagonistas & inhibidores , Ubiquitina-Proteína LigasasRESUMEN
A 60-year-old man was admitted to our hospital with fever, appetite loss, and fatigue. Chest X-ray films and computed tomography scans showed fungus-ball-like lesions in the thoracic cavity, and pleural thickening with surrounding infiltration in the left upper lobe, developing over several months. The white blood cell count (WBC) and serum C-reactive protein (CRP) levels of the patient at the time of admission were 8800/microl and 2.7 mg/dl, respectively. He showed a negative reaction for the serum Aspergillus precipitating antibody, and a positive reaction for the serum Aspergillus antigen (Pletelia Aspergillus) according to the new cut-off index (the result was 0.8). From these clinical findings, we diagnosed this lesion as chronic necrotizing pulmonary aspergillosis (CNPA) and administered anti-fungal drugs (itraconazole plus micafungin, voriconazole) for several months. Despite medication, his condition appeared to deteriorate, and Aspergillus was never confirmed from frequent sputum cultures and bronchial lavage specimens. Finally, a pneumectomy was performed. Histopathological findings revealed a Gram-positive, filament-form Actinomyces cluster inside the cavity, which we diagnosed pulmonary actinomycosis. In this case, there was a possibility that the serum aspergillus antigen showed a false-positive reaction. Case must be taken in the evaluation of serum Aspergillus antigen testing.