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1.
Nature ; 524(7563): 47-53, 2015 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-26168399

RESUMEN

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.


Asunto(s)
Genoma Humano/genética , Genómica , Neoplasias Pulmonares/genética , Mutación/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Alelos , Animales , Línea Celular Tumoral , Puntos de Rotura del Cromosoma , Ciclina D1/genética , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Sistemas Neurosecretores/metabolismo , Sistemas Neurosecretores/patología , Proteínas Nucleares/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Proteína de Retinoblastoma/genética , Transducción de Señal/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología , Proteína Tumoral p73 , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética
2.
Int J Cancer ; 146(6): 1503-1513, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-31162856

RESUMEN

In 2011, the U.S. National Lung Cancer Screening Trial (NLST) reported a 20% reduction of lung cancer mortality after regular screening by low-dose computed tomography (LDCT), as compared to X-ray screening. The introduction of lung cancer screening programs in Europe awaits confirmation of these first findings from European trials that started in parallel with the NLST. The German Lung cancer Screening Intervention (LUSI) is a randomized trial among 4,052 long-term smokers, 50-69 years of age, recruited from the general population, comparing five annual rounds of LDCT screening (screening arm; n = 2,029 participants) with a control arm (n = 2,023) followed by annual postal questionnaire inquiries. Data on lung cancer incidence and mortality and vital status were collected from hospitals or office-based physicians, cancer registries, population registers and health offices. Over an average observation time of 8.8 years after randomization, the hazard ratio for lung cancer mortality was 0.74 (95% CI: 0.46-1.19; p = 0.21) among men and women combined. Modeling by sex, however showed a statistically significant reduction in lung cancer mortality among women (HR = 0.31 [95% CI: 0.10-0.96], p = 0.04), but not among men (HR = 0.94 [95% CI: 0.54-1.61], p = 0.81) screened by LDCT (pheterogeneity = 0.09). Findings from LUSI are in line with those from other trials, including NLST, that suggest a stronger reduction of lung cancer mortality after LDCT screening among women as compared to men. This heterogeneity could be the result of different relative counts of lung tumor subtypes occurring in men and women.


Asunto(s)
Detección Precoz del Cáncer/métodos , Neoplasias Pulmonares/epidemiología , Tamizaje Masivo/métodos , Mortalidad/tendencias , Tomografía Computarizada por Rayos X , Anciano , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Incidencia , Pulmón/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/etiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores Sexuales , Fumar/efectos adversos , Análisis de Supervivencia
3.
Am J Pathol ; 187(5): 973-979, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28279655

RESUMEN

Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. COPD is characterized by chronic airway inflammation and lung infections. The airways of patients with COPD are frequently colonized with bacteria [eg, nontypeable Haemophilus influenzae (NTHi)] that cause pulmonary inflammation and exacerbations. Pulmonary adenocarcinomas are frequently associated with an activating mutation in the KRAS gene. We determined the function of Toll-like receptor (TLR) signaling on the progression of Kras-induced early adenomatous lesions in the lung. Wild-type (WT) mice and mice doubly deficient in Tlr-2 and -4 (Tlr2/4-/-), both with an oncogenic Kras allele in lung epithelium, were exposed to NTHi for 4 weeks. Exposure to NTHi resulted in increased tumor proliferation and growth in WT mice, but not in Tlr2/4-/- mice. Alveolar adenomatous hyperplasia and adenocarcinoma were significantly increased in WT mice compared with Tlr2/4-/- mice. The average size of tumors was significantly larger in WT mice, whereas there was no difference in the number of alveolar lesions between WT and Tlr2/4-/- mice. NTHi-induced pulmonary neutrophilic inflammation and tumor-associated neutrophils were reduced in Tlr2/4-/- mice. Thus, subsequent to a driver mutation, NTHi-induced inflammation promotes proliferation of early adenomatous lesions in a TLR-dependent manner.


Asunto(s)
Genes ras/fisiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Receptor Toll-Like 2/fisiología , Receptor Toll-Like 4/fisiología , Adenocarcinoma/fisiopatología , Animales , Proliferación Celular/fisiología , Infecciones por Haemophilus/fisiopatología , Haemophilus influenzae/fisiología , Neoplasias Pulmonares/fisiopatología , Ratones , Neutrófilos/fisiología , Enfermedad Pulmonar Obstructiva Crónica/virología , Transducción de Señal/fisiología , Receptor Toll-Like 2/deficiencia , Receptor Toll-Like 4/deficiencia , Proteínas ras/metabolismo
4.
RNA Biol ; 15(12): 1499-1511, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30499379

RESUMEN

Aberrant expression of noncoding RNAs plays a critical role during tumorigenesis. To uncover novel functions of long non-coding RNA (lncRNA) in lung adenocarcinoma, we used a microarray-based screen identifying LINC00673 with elevated expression in matched tumor versus normal tissue. We report that loss of LINC00673 is sufficient to trigger cellular senescence, a tumor suppressive mechanism associated with permanent cell cycle arrest, both in lung cancer and normal cells in a p53-dependent manner. LINC00673-depleted cells fail to efficiently transit from G1- to S-phase. Using a quantitative proteomics approach, we confirm the modulation of senescence-associated genes as a result of LINC00673 knockdown. In addition, we uncover that depletion of p53 in normal and tumor cells is sufficient to overcome LINC00673-mediated cell cycle arrest and cellular senescence. Furthermore, we report that overexpression of LINC00673 reduces p53 translation and contributes to the bypass of Ras-induced senescence. In summary, our findings highlight LINC00673 as a crucial regulator of proliferation and cellular senescence in lung cancer.


Asunto(s)
Senescencia Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , ARN Largo no Codificante/genética , Adenocarcinoma/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Técnicas de Silenciamiento del Gen , Humanos , Modelos Biológicos , Mutación , Interferencia de ARN , Transducción de Señal , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
5.
Int J Cancer ; 137(7): 1539-48, 2015 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-25784292

RESUMEN

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)-based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non-malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non-malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D-imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Fosfolípidos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/química , Humanos , Neoplasias Pulmonares/química , Fosfatidilinositoles/metabolismo , Fosfolípidos/química , Espectrometría de Masa por Ionización de Electrospray/métodos , Esfingomielinas/metabolismo , Espectrometría de Masas en Tándem/métodos
7.
Eur Respir J ; 43(1): 233-9, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23900983

RESUMEN

Peripheral lung lesions are sometimes difficult to reach even with endobronchial ultrasound (EBUS) and insufficient material is often obtained by transbronchial forceps biopsy. Cryoprobes can be used for performing tissue biopsies. We evaluated the safety and feasibility of the cryoprobe in combination with EBUS for the diagnosis of peripheral lung lesion. Patients with peripheral lung lesions of up to 4 cm were enrolled. After identifying the lung lesion by radial EBUS, forceps biopsies and cryobiopsies were performed in a randomised order. We evaluated safety and feasibility, and compared diagnostic yield and sample size. 39 patients were randomised and the peripheral lung lesion was reached in 31. The overall diagnostic yield was 60.5% and, in the lesions reached by EBUS, it was 74.2%. In 19 cases, the diagnosis was made with forceps as well as cryobiopsy and, in four cases, only with cryobiopsy. Cryobiopsies were significantly larger than forceps biopsies (11.17 mm(2) versus 4.69 mm(2), p<0.001). We observed one case of moderate bleeding. Transbronchial cryobiopsy with EBUS guidance is safe and useful to obtain histological samples. Larger tissue samples can be obtained by cryoprobe.


Asunto(s)
Biopsia/métodos , Broncoscopía/métodos , Criocirugía/métodos , Endosonografía/métodos , Neoplasias Pulmonares/patología , Pulmón/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia/instrumentación , Estudios de Cohortes , Criocirugía/instrumentación , Estudios de Factibilidad , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/cirugía , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Instrumentos Quirúrgicos , Tomografía Computarizada por Rayos X
8.
Eur Respir J ; 43(3): 872-83, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23988776

RESUMEN

Numerous studies have been published on single aspects of pulmonary adenocarcinoma (ADC). To comprehensively link clinically relevant ADC characteristics, we evaluated established morphological, diagnostic and predictive biomarkers in 425 resected ADCs. Morphology was reclassified. Cytokeratin-7, thyroid transcription factor (TTF)1, napsin A, thymidylate synthase and excision repair cross-complementing rodent repair deficiency complementation group-1 expression, anaplastic lymphoma kinase rearrangements as well as epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) and v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) mutations were analysed. All characteristics were correlated with clinical and survival parameters. Morphological ADC subtypes were significantly associated with smoking history and distinct patterns of diagnostic biomarkers. KRAS mutations were prevalent in male smokers, while EGFR mutations were associated with female sex, nonsmoking and lepidic as well as micropapillary growth patterns. TTF1 expression (hazard ratio (HR) for overall survival 0.61, p=0.021) and BRAF mutations (HR for disease-free survival 2.0, p=0.046) were found to be morphology- and stage-independent predictors of survival in multivariate analysis. Adjuvant radio-/chemotherapy, in some instances, strongly impacted on the prognostic effect of both diagnostic and predictive biomarkers. Our data draw a comprehensive picture of the prevalence and interplay of established histological and molecular ADC characteristics. These data will help to develop time- and cost-effective diagnostic and treatment algorithms for ADC.


Asunto(s)
Adenocarcinoma/metabolismo , Receptores ErbB/genética , Genes ras , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Tirosina Quinasas Receptoras/genética , Adulto , Anciano , Algoritmos , Quinasa de Linfoma Anaplásico , Ácido Aspártico Endopeptidasas/metabolismo , Biomarcadores/metabolismo , Análisis Costo-Beneficio , Proteínas de Unión al ADN/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunofenotipificación , Queratina-7/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Fumar , Timidilato Sintasa/metabolismo , Factores de Transcripción , Resultado del Tratamiento
9.
Histopathology ; 65(2): 187-94, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24456475

RESUMEN

AIMS: Molecular characterization of non-small-cell lung cancer (NSCLC) has revealed multiple druggable mutations for targeted therapies. Recently, chromosomal rearrangements involving c-ros oncogene 1, receptor tyrosine kinase (ROS1) were identified, and patients seem to benefit from crizotinib treatment. The aim of this study was to identify the clinicopathological characteristics of NSCLC with ROS1 expression and translocation. METHODS AND RESULTS: We screened 1478 NSCLCs with a ROS1-specific antibody, and tested positive cases with FISH. All positive cases were analysed for associated clinicopathological characteristics, including survival and molecular tumour composition. Sixty-eight cases (4.6%) showed ROS1 immunoreactivity, and ROS1 translocations were confirmed in nine cases (0.6%). ROS1 expression was predominantly found in female adenocarcinoma patients, in patients with low T stages, and in association with TTF1 and napsin expression, and certain histomorphological adenocarcinoma patterns (lepidic, acinar, and solid). ROS1 translocations occurred in conjunction with other driver mutations (EGFR, KRAS, and BRAF). ROS1 expression was found to be a stage-independent predictor of favourable survival. CONCLUSIONS: ROS1 translocations are rare events in resected NSCLCs from Caucasian patients. Immunohistochemical screening for ROS1 expression and clinicopathological parameters, including female sex, early tumour stages, adenocarcinomas with TTF1 and/or napsin expression, and a distinct histomorphological growth pattern, strongly facilitate case enrichment. Molecularly driven multistep concepts might not be optimal for case selection.


Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Proteínas Tirosina Quinasas/biosíntesis , Proteínas Proto-Oncogénicas/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Análisis de Matrices Tisulares , Translocación Genética
10.
Respiration ; 87(5): 432-8, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24457174

RESUMEN

Minimally invasive diagnostic techniques are increasingly being used to obtain specimens for pathological diagnosis and prediction. Referring to lung cancer, both endobronchial and endoesophageal ultrasound are used worldwide as diagnostic routine methods. Consequently, an increasing number of pathological samples are cytological and fewer are histological. On the other hand, the requirements for specific and sensitive tumor subtyping complemented by predictive analyses are steadily increasing and are an essential basis for evidence-based treatment decisions. In this article we focus on the cell block method as a helpful tool for diagnostic and predictive analyses in lung cancer and point out its advantages and disadvantages in comparison to conventional cytological and biopsy specimens. Furthermore, we retrospectively analyze the diagnostic results of the cell block method in a high-volume center over 5 years. The main advantages of cell blocks are the availability of established and validated protocols, archiving and the opportunity to have serial sections from the same specimens to provide or repeat molecular analyses. Actually, in case of tumor progression, even additional biomarkers can be tested using the original cell block when re-biopsies are not feasible. The cell block method should be considered as a reliable, complimentary approach to conventional cytological or biopsy procedures, which is helpful to fulfill the increasing requirements of high-quality diagnostics and prediction.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Biopsia/métodos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/métodos , Neoplasias Pulmonares/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Manejo de Especímenes/métodos , Broncoscopía , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Cohortes , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología
11.
Respiration ; 88(3): 199-207, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25115833

RESUMEN

BACKGROUND: Pirfenidone is a novel antifibrotic drug for the treatment of mild-to-moderate idiopathic pulmonary fibrosis (IPF). However, adverse events may offset treatment benefits and compliance. OBJECTIVES: To assess recent course of disease, adverse events and compliance in patients who started pirfenidone. METHODS: In an observational cohort study, 63 patients with mild-to-moderate IPF who started pirfenidone between May 2011 and June 2013 were reviewed. Pulmonary function, adverse events and treatment compliance were recorded at each clinic visit. Disease progression was defined as a reduction of vital capacity ≥10% and/or diffusion capacity (DLCO) ≥15%. RESULTS: Follow-up time on pirfenidone treatment was 11 (±7) months. Sixty-six percent of the patients continued with pirfenidone monotherapy and 34% of the patients received pirfenidone combined with corticosteroids (CCS) and/or N-acetylcysteine (NAC). There was a nonsignificant reduction in mean decline of percent predicted forced vital capacity after treatment start (0.7 ± 10.9%) compared to the pretreatment period (6.6 ± 6.7%, p = 0.098). Sixty-two percent of the patients had stable disease on pirfenidone treatment. Adverse events affected 85% of the patients, leading to discontinuation of pirfenidone in 20%. Adverse events and treatment discontinuation were seen more frequently in patients with concomitant CCS and/or NAC treatment. CONCLUSIONS: Adverse events affect the majority of patients treated with pirfenidone, but are mostly manageable with supportive measures. In this heterogeneous patient group, a nonsignificant effect of pirfenidone treatment on pulmonary function was seen, underlining the need for more data on patient selection criteria and efficacy of pirfenidone, particularly in patients with coexistent emphysema and concomitant NAC/CCS treatment.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Piridonas/uso terapéutico , Acetilcisteína/uso terapéutico , Corticoesteroides/uso terapéutico , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Erupciones por Medicamentos/etiología , Quimioterapia Combinada , Expectorantes/uso terapéutico , Fatiga/inducido químicamente , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Alemania , Humanos , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Estudios Retrospectivos , Centros de Atención Terciaria , Resultado del Tratamiento , Capacidad Vital , Pérdida de Peso
12.
Eur Respir J ; 41(3): 656-63, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22743677

RESUMEN

Basaloid carcinoma represents a rare variant of nonsmall cell lung cancer (NSCLC), which has shown a poor prognosis in a number of studies. Although it is considered to derive from a pluri- or multipotent pulmonary stem cells, little is known about the expression and clinical significance of stem cell antigens in this variant. Stage-specific embryonic antigen-4 (SSEA-4) was analysed by immunohistochemistry in 38 patients with resected early-stage basaloid NSCLC who had a median follow-up of 72.9 months. The expression of SSEA-4 was related to clinico-pathological characteristics, to the expression of the adult stem cell antigens CD117, CD133 and breast cancer resistance protein 1 (BCRP1), and to prognosis. SSEA-4 was positive in 37% of the specimens and showed no association with clinico-pathological characteristics or the expression of adult stem cell antigens. Cox proportional hazards regression analysis revealed a 6.0-fold increased risk of relapse (p = 0.001) and a 4.2-fold increased risk of disease-related mortality (p = 0.017) in SSEA-4-positive patients, while SSEA-4-negative patients showed a prognosis comparable with that of other early-stage NSCLC. SSEA-4 is expressed in a fraction of basaloid NSCLC and is associated with poor prognosis.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Antígenos Embrionarios Específico de Estadio/sangre , Antígeno AC133 , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/metabolismo , Anciano , Antígenos CD/metabolismo , Biomarcadores de Tumor/sangre , Femenino , Perfilación de la Expresión Génica , Glicoproteínas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Péptidos/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-kit/metabolismo , Transducción de Señal
13.
Eur Respir J ; 42(6): 1668-76, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23060634

RESUMEN

Patients with lung cancer are at risk of developing a second primary lung cancer (SPLC). However, the characteristics of patients at risk remain largely speculative. We reviewed 2816 lung cancer patients from our institution for the occurrence of SPLC. Any SPLC was categorised as synchronous when diagnosed within 2 years of the first primary lung cancer (FPLC) and after direct histological comparison of both tumours. All other SPLCs were considered as metachronous. 139 patients developed a second malignancy including 69 nonsmall cell lung cancer (NSCLC) and 9 small cell lung cancer. The median interval for diagnosis of metachronous SPLC (n=59) after FPLC occurrence was 72 months. SPLC detected within 5 years of FPLC diagnosis had a more favourable stage distribution (p=0.02). After diagnosis of SPLC, patients had a superior median overall survival compared to controls (57.7 versus 18.1 months; p<0.0001). Interestingly, comparing only stage IV NSCLC patients, a history of FPLC was also associated with a favourable survival (median 27.4 versus 8.97 months; p=0.007). In summary, previous lung cancer treatment does not lead to impaired prognosis after diagnosis of SPLC. Improved surveillance programmes beyond 5 years after FPLC treatment may result in more favourable disease stages for detected SPLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/secundario , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/terapia , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Riesgo , Fumar , Resultado del Tratamiento , Adulto Joven
14.
Eur Respir J ; 41(4): 943-51, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22835610

RESUMEN

Recently, a novel classification system based on tumour architecture and with high prognostic impact has been proposed for pulmonary adenocarcinomas (ADCs). For imaging-based prediction of histological ADC subtypes and, thus, prognosis, it is of paramount importance to investigate the correlations of radio- and histomorphological parameters. Associations between histomorphological ADC growth patterns (lepidic, acinar, papillary, micropapillary and solid) and data from pre-operative assessment by computed tomography (CT) imaging of 174 resected pulmonary ADCs were analysed. Margin configuration as well as solidity/ground glass opacity of an ADC was associated with distinct histomorphological ADC growth patterns. Solid-predominant ADCs usually had smooth margins and were also solid in CT scans, while lepidic-predominant ADCs had no predominant margin pattern, were located in the periphery, showed a positive bronchogram and were frequently associated with solidity/ground glass opacity. In addition, nonspherical tumour growth was a negative predictor of overall and disease-specific patient survival. We defined CT morphological parameters that were associated with histomorphological growth patterns of pulmonary ADCs. These data may form the basis for the development of future prognostic algorithms in the palliative setting, which include an integrated evaluation of biopsy histomorphology and CT scan morphology of nonresectable pulmonary ADC.


Asunto(s)
Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Pulmón/patología , Tomografía Computarizada por Rayos X , Algoritmos , Biopsia , Supervivencia sin Enfermedad , Detección Precoz del Cáncer , Humanos , Metástasis de la Neoplasia , Pronóstico , Resultado del Tratamiento
15.
Eur Respir J ; 40(5): 1221-7, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22408209

RESUMEN

Recently, a novel classification for pulmonary adenocarcinomas (ADCs) was published, the cornerstone of which is the quantification of growth patterns. Data on reproducibility in the routine diagnostic setting are lacking. 100 constitutive cases of lung ADC resection specimens from our archives were classified independently by five pulmonary pathologists and two residents according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. The most frequent predominant pattern in our cohort was solid (37%), followed by acinar (35%), lepidic (20%), papillary (5%) and micropapillary (3%). κ-values for the denomination of the predominant pattern revealed substantial agreement for pulmonary pathologists (κ=0.44-0.72) and fair agreement for residents (κ=0.38-0.47). Interobserver variability was significantly higher in cases with higher slide numbers (p=0.028) and was considerably reduced after training. Intraobserver variability was low (κ=0.79-0.87). Papillary and micropapillary patterns were the most complicated patterns to evaluate, while evaluation of lepidic and solid tumour growth was straightforward. Our data imply that the novel classification of pulmonary ADC is applicable with acceptable interobserver variability if performed by specifically trained pathologists. Additional efforts are needed to harmonise the application of this novel and clinically important classification scheme of pulmonary ADC.


Asunto(s)
Adenocarcinoma/clasificación , Adenocarcinoma/patología , Neoplasias Pulmonares/clasificación , Neoplasias Pulmonares/patología , Humanos , Variaciones Dependientes del Observador , Sociedades Médicas/estadística & datos numéricos
16.
Eur Respir J ; 39(6): 1437-42, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22075483

RESUMEN

Nonsmall cell lung cancers (NSCLCs) display a variety of morphological and molecular features. Accurate subtyping of NSCLC has been shown to predict patient survival as well as response rates and toxicities of specific drugs. Assessment of multifocal lung tumours and the distinction of synchronous primary tumours from intrapulmonary metastases represent an important problem as this decision significantly influences tumour staging and subsequent treatment strategies. In order to provide a basis for evidence-based treatment decisions in these patients, we analysed the clonal relationship of multifocal NSCLC with indistinguishable histomorphology in a series of 78 patients by allelotyping (using polymorphic short tandem repeat markers) as well as KRAS and epidermal growth factor receptor (EGFR) mutation testing. Our data demonstrate a common clonal origin indicative of intrapulmonary metastases in almost two-thirds (~62%) of the cases, while ~36% of multifocal NSCLC displayed unique molecular profiles suggesting separate primary tumours. Divergent KRAS and/or EGFR mutations were observed in ~8% of all cases. With the increased availability of EGFR-targeted therapy options, nonresectable, multifocal NSCLC with diverging KRAS and/or EGFR mutations are likely to show different treatment responses, underlining the need to separately analyse multifocal tumours. Obviously, this also holds true for further, novel molecular predictors of targeted therapies.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Femenino , Humanos , Pérdida de Heterocigocidad/genética , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Proteínas ras/genética
17.
Blood ; 116(14): 2455-61, 2010 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-20581312

RESUMEN

Cardiac biomarkers provide prognostic information in light-chain amyloidosis (AL). Thus, a novel high-sensitivity cardiac troponin T (hs-TnT) assay may improve risk stratification. hs-TnT was assessed in 163 patients. Blood levels were higher with cardiac than renal or other organ involvement and were related to the severity of cardiac involvement. Increased sensitivity was not associated with survival benefit. Forty-seven patients died during follow-up (22.3 ± 1.0 months). Nonsurvivors had higher hs-TnT than survivors. Outcome was worse if hs-TnT more than or equal to 50 ng/L and best less than 3 ng/L. Survival of patients with hs-TnT 3 to 14 ng/L did not differ from patients with moderately increased hs-TnT (14-50 ng/L), but was worse if interventricular septum was more than or equal to 15 mm. Discrimination according to the Mayo staging system was only achieved by the use of the hs-TnT assay, but not by the fourth-generation troponin T assay. Multivariate analysis revealed hs-TnT, NT-proBNP, and left ventricular impairment as independent risk factors for survival. hs-TnT and NT-proBNP predicted survival, even after exclusion of patients with impaired renal function. Plasma levels of the hs-TnT assay are associated with the clinical, morphologic, and functional severity of cardiac AL amyloidosis and could provide useful information for clinicians on cardiac involvement and outcome.


Asunto(s)
Amiloidosis/diagnóstico , Troponina T , Amiloidosis/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miocardio/patología , Pronóstico , Análisis de Supervivencia , Troponina T/sangre
18.
Histopathology ; 61(6): 1017-25, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22882703

RESUMEN

AIMS: Patient stratification according to histological subtype is important for non-small-cell lung cancer (NSCLC) therapy. For specimens with uncertain histomorphology, rational and material-saving algorithms for specific and sensitive immunotyping need to be established. METHODS AND RESULTS: One thousand one hundred and forty-five NSCLCs were immunohistochemically investigated for the expression of cytokeratin 5/6 (CK5/6), CK7, thyroid transcription factor-1 (TTF-1), p63, napsin-A, and desmocollin-3. Overall, napsin-A and desmocollin-3 were the most specific markers (specificity of each, 99%), and CK7 and CK5/6 the most sensitive markers (sensitivity, 96% and 94%) for adenocarcinomatous and squamous differentiation, respectively. However, for NSCLC not otherwise specified (NOS) cases, TTF-1, p63, CK5/6 and CK7 were found to be the most reliable markers. On the basis of morphology alone, approximately two-thirds of all NSCLCs could be reliably diagnosed in biopsy specimens. Immunohistochemistry further reduced the NOS fraction to 10%. CONCLUSIONS: When morphology alone is not reliable, the use of selected markers and marker panels is highly sensitive and specific, and allows reliable distinction between squamous cell carcinoma and adenocarcinoma. Considering the impact of typing for the selection of molecular testing and treatment response, one must be aware of immunomarker expression patterns in NSCLC and their diagnostic value, in order to optimize typing and thereby maximize patient benefit from chemotherapy.


Asunto(s)
Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/clasificación , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/clasificación , Neoplasias Pulmonares/diagnóstico , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Algoritmos , Biomarcadores/metabolismo , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Células Escamosas/patología , Diagnóstico Diferencial , Humanos , Queratina-5/metabolismo , Queratina-6/metabolismo , Queratina-7/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas de la Membrana/metabolismo , Proteínas Nucleares/metabolismo , Estudios Retrospectivos , Sensibilidad y Especificidad , Factor Nuclear Tiroideo 1 , Factores de Transcripción/metabolismo
19.
Histopathology ; 61(3): 465-72, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22463725

RESUMEN

AIMS: Pemetrexed (Pem) is a potent inhibitor of thymidylate synthase (TS), and has shown efficacy in the treatment of non-small-cell lung cancer (NSCLC). TS expression in NSCLC biopsy specimens may correlate with the tumour responses to TS-inhibiting agents. As TS is not homogeneously expressed, our aim was to test whether TS expression in biopsy specimens may be representative for the whole tumour and can be used for therapeutic assessment. METHODS AND RESULTS: We immunohistochemically analysed TS expression in biopsy and corresponding resection specimens of 100 consecutive NSCLCs. The samples were subgrouped according to TS expression levels, and the degree of agreement between the biopsy and the corresponding resection specimen was calculated. TS expression-based grouping according to one cut-off criterion (high or low expression) led to concordant results between biopsy and resection specimens. When more than one cut-off criterion was used, the results were significantly different. CONCLUSIONS: Thymidylate synthase expression levels in NSCLC biopsy specimens may correspond to TS expression of the whole tumour when robust scoring systems are applied. Further studies are needed to determine whether high or low TS expression in NSCLC biopsy specimens is of predictive value, and whether it may allow the selection of patients who will benefit from Pem treatment.


Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Neoplasias Pulmonares/enzimología , Timidilato Sintasa/análisis , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/cirugía , Timidilato Sintasa/biosíntesis
20.
BMC Cancer ; 11: 161, 2011 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-21548930

RESUMEN

BACKGROUND: Aquaporins (AQPs) have been recognized to promote tumor progression, invasion, and metastasis and are therefore recognized as promising targets for novel anti-cancer therapies. Potentially relevant AQPs in distinct cancer entities can be determined by a comprehensive expression analysis of the 13 human AQPs. METHODS: We analyzed the presence of all AQP transcripts in 576 different normal lung and non-small cell lung cancer (NSCLC) samples using microarray data and validated our findings by qRT-PCR and immunohistochemistry. RESULTS: Variable expression of several AQPs (AQP1, -3, -4, and -5) was found in NSCLC and normal lung tissues. Furthermore, we identified remarkable differences between NSCLC subtypes in regard to AQP1, -3 and -4 expression. Higher transcript and protein levels of AQP4 in well-differentiated lung adenocarcinomas suggested an association with a more favourable prognosis. Beyond water transport, data mining of co-expressed genes indicated an involvement of AQP4 in cell-cell signalling, cellular movement and lipid metabolism, and underlined the association of AQP4 to important physiological functions in benign lung tissue. CONCLUSIONS: Our findings accentuate the need to identify functional differences and redundancies of active AQPs in normal and tumor cells in order to assess their value as promising drug targets.


Asunto(s)
Acuaporina 4/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Perfilación de la Expresión Génica , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Análisis por Matrices de Proteínas
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