Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Pulmonares , Neoplasias Primarias Secundarias , Nivolumab , Neoplasias Nasales , Plasmacitoma , Anciano , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/patología , Humanos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Masculino , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Primarias Secundarias/patología , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Neoplasias Nasales/tratamiento farmacológico , Neoplasias Nasales/patología , Plasmacitoma/tratamiento farmacológico , Plasmacitoma/patologíaRESUMEN
Cutaneous angiosarcoma (CA) is extremely rare, and little is known about the biological significance of possible biomarkers for chemotherapeutic agents. Thymidylate synthase (TS) is an attractive target for cancer treatment in various human neoplasms. It remains unclear whether the expression of TS is associated with the clinicopathological features of CA patients. The aim of this study was to elucidate the relationship between TS expression and the clinicopathological significance in CA patients. Fifty-one patients with CA were included in this study. TS expression and Ki-67 labeling index were examined using immunohistochemical analysis. TS was positively expressed in 39% (20/51) of CA patients. No statistically significant prognostic factor was identified as a predictor of overall survival (OS) for all patients by univariate analysis, whereas a significant prognostic variable for progression free survival (PFS) was found to be the clinical stage. In addition, both univariate and multivariate analyses confirmed that positive expression of TS was a significant predictor of worse PFS in CA patients of clinical stage 1. CONCLUSION: Positive TS expression in CA was identified as a significant predictor of worse outcome in patients of clinical stage 1.
Asunto(s)
Hemangiosarcoma/enzimología , Neoplasias Cutáneas/enzimología , Timidilato Sintasa/metabolismo , Humanos , Inmunohistoquímica , Pronóstico , Supervivencia sin Progresión , Tasa de SupervivenciaRESUMEN
L-type amino acid transporter 1 (LAT1) and CD98 are frequently expressed in various human cancers, and closely correlated with tumor aggressiveness and survival. However, little is known about the expression of LAT1 and CD98 in cutaneous angiosarcoma. The aim of this study is to investigate the clinicopathological significance of these markers in the dismal disease. A total of 52 patients with cutaneous angiosarcoma were retrospectively reviewed. Immunohistochemical staining of tumor specimens were evaluated using anti-LAT1, CD98 and Ki-67 antibodies. The rates of high expression for LAT1 and CD98 were 56% (29/52) and 79% (41/52), respectively. The frequency of high expression for CD98 was significantly higher than that for LAT1 (p=0.021). The low expression of CD98 was significantly associated with distant metastasis (p=0.044) and was identified as a significant prognostic predictor by multivariate analysis. The expression level of LAT1 was not significantly correlated with prognosis. The low expression of CD98 is a novel biomarker for predicting poor prognosis in patients with cutaneous angiosarcoma.
Asunto(s)
Proteína-1 Reguladora de Fusión/genética , Hemangiosarcoma/genética , Transportador de Aminoácidos Neutros Grandes 1/genética , Biomarcadores de Tumor/genética , Hemangiosarcoma/diagnóstico , Humanos , Pronóstico , Estudios RetrospectivosAsunto(s)
Estrés del Retículo Endoplásmico/genética , Epidermólisis Ampollosa Distrófica/genética , Adulto , Sustitución de Aminoácidos/genética , Colágeno Tipo VII/genética , Chaperón BiP del Retículo Endoplásmico , Epidermólisis Ampollosa Distrófica/patología , Femenino , Células HEK293 , Proteínas de Choque Térmico/genética , Humanos , Queratinocitos , Microscopía Electrónica de Transmisión , Mutación/genética , Transfección , Regulación hacia ArribaRESUMEN
The glucose-regulated protein (GRP78/BiP) and PKR-like endoplasmic reticulum kinase (PERK) plays a crucial role in the endoplasmic reticulum (ER) stress response. GRP78/BiP is highly elevated in various human cancers. Our study is to examine the clinicopathological significance of GRP78/BiP and PERK expression in patients with tongue cancer. A total of 85 tongue cancer patients were analyzed, and tumor specimens were stained by immunohistochemistry for GRP78/BiP, PERK, GLUT1, Ki-67 and microvessel density (MVD) determined by CD34.GRP78/BiP and PERK were highly expressed in 47% and 35% of all patients, respectively. GRP78/BiP disclosed a significant relationship with PERK expression, lymphatic permeation, vascular invasion, glucose metabolism and cell proliferation. The expression of GRP78/BiP was significantly higher in metastatic sites than in primary sites (79% vs. 47%, p=0.003). We found that the high expression of GRP78/BiP was proven to be an independent prognostic factor for predicting poor outcome in patients with tongue cancer. In the analysis of PFS, PERK was identified as an independent predictor. The increased GRP78/BiP expression was clarified as an independent prognostic marker for predicting worse outcome. Our study suggests that the expression of GRP78/BiP as ER stress marker is important in the pathogenesis and development of tongue cancer.
Asunto(s)
Estrés del Retículo Endoplásmico/fisiología , Proteínas de Choque Térmico/metabolismo , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/patología , eIF-2 Quinasa/metabolismo , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Chaperón BiP del Retículo Endoplásmico , Femenino , Humanos , Inmunohistoquímica , Masculino , PronósticoRESUMEN
The immunoglobulin heavy chain binding protein (BiP)/glucose-regulated protein 78 (GRP78) plays an essential role in the endoplasmic reticulum (ER) stress, and GRP78/BiP is known to be highly expressed in various human neoplasms. The clinicopathological features of GRP78/BiP expression in patients with advanced hypopharyngeal squamous cell carcinoma (HSCC) remain unclear. The aim of this study is to elucidate the prognostic significance of GRP78/BiP for HSCC.A total of 68 patients with advanced HSCC (stage III/IV) were analyzed, and tumor specimens were stained with immunohistochemistry for GRP78/BiP, Ki-67, and microvessel density (MVD), as determined through CD34 and p53 levels. GRP78/BiP was highly expressed in 80.8% (55/68) of all patients. The expression level of GRP78/BiP disclosed no significant relationship with any variables. Multivariate analysis confirmed that low expression of GRP78/BiP was an independent prognostic factor for predicting poor overall survival and progression-free survival in patients with advanced HSCC. The decreasing expression of GRP78/BiP was identified as a significant predictor related to shorter survival duration after surgery for advanced HSCC. Our study suggests that the reduced expression of GRP78/BiP contributes to worse survival for patients with advanced head and neck cancer.
Asunto(s)
Proteínas de Choque Térmico/biosíntesis , Neoplasias Hipofaríngeas/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Femenino , Humanos , Neoplasias Hipofaríngeas/irrigación sanguínea , Neoplasias Hipofaríngeas/patología , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Supervivencia sin Progresión , Carcinoma de Células Escamosas de Cabeza y Cuello/irrigación sanguínea , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
Thymidylate synthase (TS) plays an essential role in the pathogenesis and development of cancer, and TS-targeting agents have been widely used against different types of cancers. However, it remains still unclear whether or not TS is expressed in malignant melanoma. We conducted the clinicopathological study to investigate the prognostic significance of TS expression in cutaneous malignant melanoma. Ninety-nine patients with surgically resected cutaneous malignant melanoma were assessed. Tumor sections were stained by immunohistochemistry for TS, Ki-67, and microvessel density (MVD) determined by CD34. TS was positively expressed in 26% (26 out of 99). The expression of TS was significantly associated with T factor, cell proliferation (Ki-67) and MVD (CD34). By Spearman's rank test, TS expression was significantly correlated with Ki67 and CD34. By univariate analysis, ulceration, disease stage, TS, Ki-67 and CD34 had a significant relationship with survival. Multivariate analysis confirmed that TS was an independent prognostic factor for poor prognosis of cutaneous malignant melanoma. The positive expression of TS could be a useful marker for predicting poor prognosis in patients with cutaneous malignant melanoma, and TS-targeting agents may be worth trying for the treatment of this dismal disease.
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Biomarcadores de Tumor/metabolismo , Melanoma/mortalidad , Melanoma/patología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Timidilato Sintasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/metabolismo , Carcinogénesis/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Masculino , Melanoma/genética , Persona de Mediana Edad , Neoplasias Cutáneas/genética , Timidilato Sintasa/biosíntesis , Timidilato Sintasa/genética , Resultado del Tratamiento , Melanoma Cutáneo MalignoRESUMEN
Purpose. Gefitinib is an effective first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, whether second-line platinum combination chemotherapy after first-line gefitinib treatment shows similar effects to first-line platinum combination chemotherapy in these patients remains unclear. Therefore, we here aimed to investigate the efficacy of platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations. Methods/patients. We retrospectively evaluated the clinical effects of second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations (exon 19 deletion or exon 21 L858R mutation) at five institutions. All patients were initially treated with gefitinib (250 mg/day) followed by platinum combination chemotherapy as second-line chemotherapy. Results. Between January 2006 and December 2012, 42 patients [8 men, 34 women; median age, 63 years (range 3975 years)] were enrolled. The overall response rate, disease control rate, and median progression-free survival (PFS) were 26.2, 61.9 %, and 5.1 months, respectively, after the second-line treatment. The corresponding values for first-line gefitinib treatment were 69.0, 95.2 %, and 11.1 months, respectively. Moreover, second-line platinum combination chemotherapy with pemetrexed or bevacizumab-containing regimens was independently associated with improved PFS. Conclusions. Second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations was effective and showed equivalent outcomes to first-line platinum combination chemotherapy. After failure of first-line gefitinib therapy, second-line platinum combination chemotherapy with pemetrexed or bevacizumab might result in improved PFS (AU)
No disponible
Asunto(s)
Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Combinada , Compuestos de Platino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Genes erbB-1 , Adenocarcinoma/tratamiento farmacológico , Estudios Retrospectivos , Mutagénesis , Carboplatino/uso terapéutico , Estimación de Kaplan-MeierRESUMEN
PURPOSE: Gefitinib is an effective first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, whether second-line platinum combination chemotherapy after first-line gefitinib treatment shows similar effects to first-line platinum combination chemotherapy in these patients remains unclear. Therefore, we here aimed to investigate the efficacy of platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations. METHODS/PATIENTS: We retrospectively evaluated the clinical effects of second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations (exon 19 deletion or exon 21 L858R mutation) at five institutions. All patients were initially treated with gefitinib (250 mg/day) followed by platinum combination chemotherapy as second-line chemotherapy. RESULTS: Between January 2006 and December 2012, 42 patients [8 men, 34 women; median age, 63 years (range 39-75 years)] were enrolled. The overall response rate, disease control rate, and median progression-free survival (PFS) were 26.2, 61.9%, and 5.1 months, respectively, after the second-line treatment. The corresponding values for first-line gefitinib treatment were 69.0, 95.2%, and 11.1 months, respectively. Moreover, second-line platinum combination chemotherapy with pemetrexed or bevacizumab-containing regimens was independently associated with improved PFS. CONCLUSIONS: Second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations was effective and showed equivalent outcomes to first-line platinum combination chemotherapy. After failure of first-line gefitinib therapy, second-line platinum combination chemotherapy with pemetrexed or bevacizumab might result in improved PFS.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Mutación/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Bevacizumab/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Estudios de Seguimiento , Gefitinib , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Pemetrexed/administración & dosificación , Pronóstico , Quinazolinas/administración & dosificación , Estudios Retrospectivos , Tasa de Supervivencia , GemcitabinaRESUMEN
BACKGROUND: The association between human papillomavirus (HPV) and squamous cell carcinoma (SCC) has been reported; however, the prevalence of HPV infection varies, and the clinical characteristics of HPV-positive cases remain unknown. OBJECTIVES: To elucidate the frequency of HPV infection in a series of Japanese patients with SCC and to identify the characteristics of HPV-positive cases. METHODS: We evaluated 38 patients with SCC treated at our department. HPV typing was performed using SCC samples from different body sites. Immunohistochemical staining for HPV proteins and p16(INK) (4a) was performed, in addition to polymerase chain reaction and in situ hybridization. The clinical characteristics of the HPV-positive cases were clarified. RESULTS: Two genital lesions were positive for HPV type 16. Both cases showed basaloid features histopathologically, and were considered to have SCC that had arisen from bowenoid papulosis. p16(INK) (4a) expression was observed in 11 cases, including the two HPV-positive cases. CONCLUSIONS: The present study indicates that the prevalence of HPV is not high and that bowenoid papulosis is an HPV-associated precancerous lesion. Further investigation is necessary to assess the relationship between HPV infection and SCC.
Asunto(s)
Carcinoma de Células Escamosas/virología , Papillomavirus Humano 16/aislamiento & purificación , Infecciones por Papillomavirus/complicaciones , Neoplasias Cutáneas/virología , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , ADN Viral/aislamiento & purificación , Femenino , Papillomavirus Humano 16/genética , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Papillomavirus/patología , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Amino-acid transporters are necessary for the tumour cell growth and survival, and have a crucial role in the development and invasiveness of cancer cells. But, it remains unclear about the prognostic significance of L-type amino-acid transporter 1 (LAT1), system ASC amino-acid transporter-2 (ASCT2), and xCT expression in patients with tongue cancer. We conducted the clinicopathological study to investigate the protein expression of these amino-acid transporters in tongue cancer. METHODS: Eighty-five patients with surgically resected tongue cancer were evaluated. Tumour sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67, and microvessel density (MVD) determined by CD34, and p53. RESULTS: L-type amino-acid transporter 1 and 4F2hc were highly expressed in 61% (52 out of 85) and 45% (38 out of 47), respectively. ASC amino-acid transporter-2 and xCT were positively expressed in 59% (50 out of 85) and 21% (18 out of 85), respectively. The expression of both LAT1 and ASCT2 was significantly associated with disease staging, lymph-node metastasis, lymphatic permeation, 4F2hc expression and cell proliferation (Ki-67). xCT expression indicated a significant association with advanced stage and tumour factor. By univariate analysis, disease staging, lymphatic permeation, vascular invasion, LAT1, ASCT2, 4F2hc, and Ki-67 had a significant relationship with overall survival. Multivariate analysis confirmed that LAT1 was an independent prognostic factor for predicting poor prognosis. CONCLUSIONS: L-type amino-acid transporter 1 and ASCT2 can serve as a significant prognostic factor for predicting worse outcome after surgical treatment and may have an important role in the development and aggressiveness of tongue cancer.
Asunto(s)
Sistema de Transporte de Aminoácidos ASC/análisis , Sistema de Transporte de Aminoácidos y+/análisis , Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/química , Transportador de Aminoácidos Neutros Grandes 1/análisis , Proteínas de Neoplasias/análisis , Neoplasias de la Lengua/química , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/cirugía , Quimioterapia Adyuvante , Terapia Combinada , Supervivencia sin Enfermedad , Docetaxel , Combinación de Medicamentos , Femenino , Cadena Pesada de la Proteína-1 Reguladora de Fusión/análisis , Humanos , Estimación de Kaplan-Meier , Antígeno Ki-67/análisis , Metástasis Linfática , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Estadificación de Neoplasias , Ácido Oxónico/administración & dosificación , Pronóstico , Taxoides/administración & dosificación , Tegafur/administración & dosificación , Neoplasias de la Lengua/irrigación sanguínea , Neoplasias de la Lengua/tratamiento farmacológico , Neoplasias de la Lengua/cirugía , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/análisisRESUMEN
BACKGROUND: ASC amino-acid transporter 2 (ASCT2) is a major glutamine transporter that has an essential role in tumour growth and progression. Although ASCT2 is highly expressed in various cancer cells, the clinicopathological significance of its expression in non-small cell lung cancer (NSCLC) remains unclear. METHODS: One hundred and four patients with surgically resected NSCLC were evaluated as one institutional cohort. Tumour sections were stained by immunohistochemistry (IHC) for ASCT2, Ki-67, phospho-mTOR (mammalian target of rapamycin), and CD34 to assess the microvessel density. Two hundred and four patients with NSCLC were also validated by IHC from an independent cohort. RESULTS: ASC amino-acid transporter 2 was expressed in 66% of patients, and was closely correlated with disease stage, lymphatic permeation, vascular invasion, CD98, cell proliferation, angiogenesis, and mTOR phosphorylation, particularly in patients with adenocarcinoma (AC). Moreover, two independent cohorts confirmed that ASCT2 was an independent marker for poor outcome in AC patients. CONCLUSIONS: ASC amino-acid transporter 2 expression has a crucial role in the metastasis of pulmonary AC, and is a potential molecular marker for predicting poor prognosis after surgery.
Asunto(s)
Sistema de Transporte de Aminoácidos ASC/genética , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Pronóstico , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Metástasis de la Neoplasia/genéticaRESUMEN
BACKGROUND: On the basis of our recent findings of oncogenic KRAS-induced interleukin-8 (IL-8) overexpression in non-small cell lung cancer, we assessed the clinicopathological and prognostic significances of IL-8 expression and its relationship to KRAS mutations in lung adenocarcinomas. METHODS: IL-8 expression was examined by quantitative RT-PCR using 136 of surgical specimens from lung adenocarcinoma patients. The association between IL-8 expression, clinicopathological features, KRAS or EGFR mutation status and survival was analysed. RESULTS: IL-8 was highly expressed in tumours from elderly patients or smokers and in tumours with pleural involvement or vascular invasion. In a non-smokers' subgroup, IL-8 level positively correlated with age. IL-8 was highly expressed in tumours with KRAS mutations compared with those with EGFR mutations or wild-type EGFR/KRAS. Lung adenocarcinoma patients with high IL-8 showed significantly shorter disease-free survival (DFS) and overall survival (OS) than those with low IL8. DFS and OS were significantly shorter in the patients with mutant KRAS/high IL-8 than in those with wild-type KRAS/low IL-8. Cox regression analyses demonstrated that elevated IL-8 expression correlated with unfavourable prognosis. CONCLUSIONS: Our findings suggest that IL-8 expression is associated with certain clinicopathological features including age and is a potent prognostic marker in lung adenocarcinoma, especially in oncogenic KRAS-driven adenocarcinoma.
Asunto(s)
Adenocarcinoma/genética , Interleucina-8/biosíntesis , Neoplasias Pulmonares/genética , Pronóstico , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adenocarcinoma del Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-8/genética , Estimación de Kaplan-Meier , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas p21(ras)RESUMEN
PURPOSE: (18)F-FAMT as an amino-acid tracer for positron emission tomography (PET) is useful for detecting human neoplasms. (18)F-FAMT is accumulated in tumour cells solely via L-type amino-acid transporter 1 (LAT1). This study was conducted to investigate the biological significance of (18)F-FAMT uptake in patients with oesophageal cancer. METHODS: From April 2008 to December 2011, 42 patients with oesophageal cancer underwent both (18)F-FAMT PET/CT and (18)F-FDG PET/CT before surgical treatment. The immunohistochemical analysis of LAT1, CD98, Ki-67, CD34, p53, p-Akt and p-mTOR was performed on the primary lesions. In vitro experiments were performed to examine the mechanism of (18)F-FAMT uptake. RESULTS: High uptake of (18)F-FAMT was significantly associated with advanced stage, lymph node metastasis and the expression of LAT1, CD98, Ki-67 and CD34. LAT1 expression yielded a statistically significant correlation with CD98 expression, cell proliferation, angiogenesis and glucose metabolism. In vitro experiments revealed that (18)F-FAMT was specifically transported by LAT1. CONCLUSIONS: The uptake of (18)F-FAMT within tumour cells is determined by the LAT1 expression and correlated with cell proliferation and angiogenesis in oesophageal cancer. The present experiments also confirmed the presence of LAT1 as an underlying mechanism of (18)F-FAMT accumulation.
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Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Radioisótopos de Flúor , Metástasis Linfática/diagnóstico , Tomografía de Emisión de Positrones/métodos , Anciano , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/patología , Femenino , Radioisótopos de Flúor/administración & dosificación , Regulación Neoplásica de la Expresión Génica , Humanos , Transportador de Aminoácidos Neutros Grandes 1/biosíntesis , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Metástasis Linfática/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Radiografía , Radiofármacos/administración & dosificaciónRESUMEN
KRAS mutations are one of the most common driver mutations in non-small-cell lung cancer (NSCLC) and finding druggable target molecules to inhibit oncogenic KRAS signaling is a significant challenge in NSCLC therapy. We recently identified epiregulin (EREG) as one of several putative transcriptional targets of oncogenic KRAS signaling in both KRAS-mutant NSCLC cells and immortalized bronchial epithelial cells expressing ectopic mutant KRAS. In the current study, we found that EREG is overexpressed in NSCLCs harboring KRAS, BRAF or EGFR mutations compared with NSCLCs with wild-type KRAS/BRAF/EGFR. Small interfering RNAs (siRNAs) targeting mutant KRAS, but not an siRNA targeting wild-type KRAS, significantly reduced EREG expression in KRAS-mutant and EREG-overexpressing NSCLC cell lines. In these cell lines, EREG expression was downregulated by MEK and ERK inhibitors. Importantly, EREG expression significantly correlated with KRAS expression or KRAS copy number in KRAS-mutant NSCLC cell lines. Further expression analysis using 89 NSCLC specimens showed that EREG was predominantly expressed in NSCLCs with pleural involvement, lymphatic permeation or vascular invasion and in KRAS-mutant adenocarcinomas. In addition, multivariate analysis revealed that EREG expression is an independent prognostic marker and EREG overexpression in combination with KRAS mutations was associated with an unfavorable prognosis for lung adenocarcinoma patients. In KRAS-mutant and EREG overexpressing NSCLC cells, siRNA-mediated EREG silencing inhibited anchorage-dependent and -independent growth and induced apoptosis. Our findings suggest that oncogenic KRAS-induced EREG overexpression contributes to an aggressive phenotype and could be a promising therapeutic target in oncogenic KRAS-driven NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Factor de Crecimiento Epidérmico/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Anciano , Apoptosis/genética , Butadienos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular , Línea Celular Tumoral , Factor de Crecimiento Epidérmico/metabolismo , Epirregulina , Receptores ErbB/genética , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Nitrilos/farmacología , Fenotipo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras) , Pirazoles/farmacología , Piridazinas/farmacología , Interferencia de ARN , Proteínas ras/metabolismoRESUMEN
BACKGROUND: The expression of L-type amino-acid transporter 1 (LAT1) is tumour-specific and has been shown to have essential roles in cell growth and survival. However, little is known regarding the clinical significance of LAT1 expression in pancreatic cancer. This study was conducted to determine the prognostic significance of LAT1 expression. METHODS: A total of 97 consecutive patients with surgically resected pathological stage I-IV pancreatic ductal adenocarcinoma were retrospectively reviewed. Tumour sections were stained by immunohistochemistry for LAT1, CD98, Ki-67 and vascular endothelial growth factor (VEGF), and microvessel density was determined by CD34 and p53. RESULTS: L-type amino-acid transporter 1 and CD98 were highly expressed in 52.6% (51/97) and 56.7% (55/97) of cases, respectively (P=0.568). The expression of LAT1 within pancreatic cancer cells was significantly associated with disease stage, tumour size, Ki-67, VEGF, CD34, p53 and CD98. L-type amino-acid transporter 1 expression was confirmed to be a significant prognostic factor for predicting poor outcome by multivariate analysis. CONCLUSION: L-type amino-acid transporter 1 expression is a promising pathological marker for the prediction of outcome in patients with pancreatic cancer.
Asunto(s)
Carcinoma Ductal Pancreático/metabolismo , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Neoplasias Pancreáticas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Supervivencia sin Enfermedad , Femenino , Proteína-1 Reguladora de Fusión/metabolismo , Humanos , Inmunohistoquímica , Masculino , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , PronósticoRESUMEN
The aim of this study is to examine the relationship between the expression level of excision repair cross-complementation group 1 (ERCC1) and of 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET) in various thoracic neoplasm.Three hundreds-eight patients [non-small cell lung cancer (NSCLC)(n=56), malignant pleural mesothelioma (MPM)(n=21), pulmonary metastatic tumors (PMT)(n=148), thymic epithelial tumors (n=49) and pulmonary neuroendocrine tumor (n=34)] who underwent 18F-FDG PET before treatment were included in this study. Tumors sections were stained by immunohistochemistry for ERCC1, glucose transporter 1(Glut1), vascular endothelial growth factor (VEGF) and microvessel density (MVD) by determinate by CD34. The expression of ERCC1 in thoracic neoplasms had a positivity of 49% (152/308), and the positive rates of ERCC1 expression in NSCLC, PMT, thymic epithelial tumor, pulmonary neuroendocrine tumor and MPM were 52, 43, 53, 47 and 85%, respectively. The positivity of ERCC1 expression was significantly higher in MPM and SQC than in the other histological types. A statistically significant correlation between ERCC1 expression and 18F-FDG uptake was observed in thymic epithelial tumors, especially thymoma. Moreover, ERCC1 expression was also closely associated with the expression of Glut1, VEGF and MVD.Our results indicated that 18F-FDG uptake may be an alternative biomarker for predicting ERCC1 expression in patients with thymoma.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Endonucleasas/metabolismo , Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Radiofármacos , Neoplasias Torácicas/diagnóstico por imagen , Neoplasias Torácicas/metabolismo , Anciano , Antígenos CD34/metabolismo , Femenino , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Técnicas para Inmunoenzimas , Masculino , Neoplasias Torácicas/patología , Neoplasias del Timo/diagnóstico por imagen , Neoplasias del Timo/metabolismo , Neoplasias del Timo/patología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Oxidative stress plays an important role in the pathogenesis of asthma. Interestingly, a low airway pH and a high concentration of 8-isoprostane, a marker of oxidative stress, has been reported to cause inflammatory airway diseases. However, the relationship between these 2 markers and pulmonary function has not been determined in mild asthma patients. METHODS: pH and 8-isoprostane concentration were measured in exhaled breath condensate (EBC) from patients with mild asthma (n = 44) and healthy subjects (n = 20). The relationship between acid stress (pH) and oxidative stress (8-isoprostane) was then analyzed, along with the relationships between these 2 markers and lung function. RESULTS: The median (interquartile range [IQR]) pH of EBC was significantly lower in asthma patients than in control subjects (7.53 [7.41-7.68] vs 7.70 [7.62-7.74], P < .05), while the median (IQR) 8-isoprostane concentration of EBC was significantly higher in asthma patients than control subjects (16.2 [11.7-19.1] vs 3.5 [2.6-7.9] pg/mL, P < .05). There was no correlation between pH and 8-isoprostane concentration. Furthermore, lung function was not correlated with either pH or 8-isoprostane concentrations in EBC. CONCLUSIONS: Acid stress and oxidative stress assessed by pH and 8-isoprostane concentration, respectively, in EBC did not show parallel changes associated with asthma and were not correlated with lung function in asthma patients. These 2 stress factors may have different roles in the pathogenesis of asthma.
Asunto(s)
Asma/metabolismo , Concentración de Iones de Hidrógeno , Estrés Oxidativo , Adulto , Pruebas Respiratorias , Dinoprost/análogos & derivados , Dinoprost/análisis , Femenino , Humanos , MasculinoRESUMEN
The clinical significance of L-type amino acid transporter 1 (LAT1) expression remains unclear, whereas many experimental studies have demonstrated that LAT1 is associated with the proliferation of cancer cells. The purpose of this study was to evaluate the prognostic value of LAT1 in patients with nonsmall cell lung cancer (NSCLC). A total of 321 consecutive patients with completely resected pathologic stage I-III NSCLC were retrospectively reviewed. Expression of LAT1 and proliferative activity, as determined by the Ki-67 labelling index, was also evaluated immunohistochemically and correlated with the prognosis of patients who underwent complete resection of the tumour. Expression of LAT1 was positive in 163 patients (51%) (29% of adenocaricnoma (58 of 200 patients), 91% of squamous cell carcinoma (91 of 100 patients), and 67% of large cell carcinoma (14 of 21 patients)). The 5-year survival rate of LAT1-positive patients (51.8%) was significantly worse than that of LAT1-negative patients (87.8%; P<0.001). L-type amino acid transporter 1 expression was significantly associated with lymph node metastasis and disease stage. Multivariate analysis confirmed that positive expression of LAT1 was an independent factor for predicting a poor prognosis. There was a significant correlation between LAT1 expression and Ki-67 labelling index. LAT1 expression is a promising pathological factor to predict the prognosis in patients with resectable stage I-III NSCLC.