Hemotórax masivo espontáneo en pacientes con neurofibromatosis tipo 1 / Massive spontaneous hemothorax in patients with neurofibromatosis type 1

El hemotórax espontáneo es una entidad poco frecuente que en los pacientes con antecedentes de neurofibromatosis tipo 1 (NF1) puede ser debido a malformaciones vasculares intratorácicas que predisponen a formaciones aneurismáticas o bien a sangrado de tumores torácicos. Esto ocurre en muy raras ocasiones, con solo 53 casos reportados en la bibliografía desde 1975. Presentamos dos casos: el primero, un varón de 73 años con hemotorax derecho secundario a un neurofibroma intercostal; el segundo, una mujer de 35 años con hemotórax izquierdo secundario a un neurofibroma que lesionaba la arteria mamaria interna. Revisando la bibliografía, el 61,8% son mujeres con una edad media de 43,9 años, y con cierta predisposición a la localización en el hemitórax izquierdo (56,4%). El paquete intercostal es el más frecuentemente involucrado en el sangrado. La cirugía ha sido el tratamiento realizado con mayor frecuencia (58,2%), si bien la embolización a través de arteriografía selectiva es un tratamiento válido. Un 30,9% fallecieron durante el episodio y aquellos tratados con cirugía o embolización arteriográfica tienen una mayor supervivencia que aquellos pacientes a los que no recibieron tratamiento invasivo o bien solo se les colocó un drenaje torácico (p = 0,02)

Spontaneous hemothorax is an uncommon event that can occur in patients with a history of neurofibromatosis type 1 because of intrathoracic vascular malformations that predispose to aneurysms or bleeding from thoracic tumors. Only 53 cases of this rare association have been reported in the literature since 1975. We described 2 cases: one patient was a 73-year-old man with a right hemothorax secondary to an intercostal neurofibroma; the other was a 35-year-old woman with a left hemothorax secondary to a neurofibroma that compromised the internal mammary artery. Our review of the literature found that 61.8% of cases involved women with a mean age of 43.9 years. There was a certain tendency toward left-sided (56.4%) hemothorax, and the intercostal space was the most common site of bleeding. Treatment was most often surgical (58.2%) in reported cases, although selective artery embolization is also a valid choice. Exitus occurred during 30.9% of the reported episodes, and survival was higher in patients who were treated with surgery or arterial embolization than in those in whom only a thoracic drain was placed or who received no invasive treatment (P=.02)

Massive spontaneous hemothorax in patients with neurofibromatosis type 1. / Hemotórax masivo espontáneo en pacientes con neurofibromatosis tipo 1.

OBJECTIVES: Spontaneous hemothorax is an uncommon event that can occur in patients with a history of neurofibromatosis type 1 because of intrathoracic vascular malformations that predispose to aneurysms or bleeding from thoracic tumors. Only 53 cases of this rare association have been reported in the literature since 1975. We described 2 cases: one patient was a 73-year-old man with a right hemothorax secondary to an intercostal neurofibroma; the other was a 35-year-old woman with a left hemothorax secondary to a neurofibroma that compromised the internal mammary artery. Our review of the literature found that 61.8% of cases involved women with a mean age of 43.9 years. There was a certain tendency toward left-sided (56.4%) hemothorax, and the intercostal space was the most common site of bleeding. Treatment was most often surgical (58.2%) in reported cases, although selective artery embolization is also a valid choice. Exitus occurred during 30.9% of the reported episodes, and survival was higher in patients who were treated with surgery or arterial embolization than in those in whom only a thoracic drain was placed or who received no invasive treatment (P=.02).

ES: El hemotórax espontáneo es una entidad poco frecuente que en los pacientes con antecedentes de neurofibromatosis tipo 1 (NF1) puede ser debido a malformaciones vasculares intratorácicas que predisponen a formaciones aneurismáticas o bien a sangrado de tumores torácicos. Esto ocurre en muy raras ocasiones, con solo 53 casos reportados en la bibliografía desde 1975. Presentamos dos casos: el primero, un varón de 73 años con hemotorax derecho secundario a un neurofibroma intercostal; el segundo, una mujer de 35 años con hemotórax izquierdo secundario a un neurofibroma que lesionaba la arteria mamaria interna. Revisando la bibliografía, el 61,8% son mujeres con una edad media de 43,9 años, y con cierta predisposición a la localización en el hemitórax izquierdo (56,4%). El paquete intercostal es el más frecuentemente involucrado en el sangrado. La cirugía ha sido el tratamiento realizado con mayor frecuencia (58,2%), si bien la embolización a través de arteriografía selectiva es un tratamiento válido. Un 30,9% fallecieron durante el episodio y aquellos tratados con cirugía o embolización arteriográfica tienen una mayor supervivencia que aquellos pacientes a los que no recibieron tratamiento invasivo o bien solo se les colocó un drenaje torácico (p = 0,02).

Benchmarking en cirugía torácica. Tercera edición / Benchmarking in Thoracic Surgery. Third Edition

Introducción: Benchmarking hace referencia a la comparación continuada de la eficiencia y la calidad entre productos y actividades con el objetivo fundamental de alcanzar la excelencia. Objetivo: Analizar los resultados del benchmarking realizado en 2013 con la actividad asistencial de Cirugía Torácica en el año 2012 en 17 servicios de Cirugía Torácica españoles participantes. Métodos: La fuente de información para el estudio ha sido el conjunto mínimo básico de datos de hospitalización correspondiente al año 2012. Los datos han sido proporcionados por los centros participantes, a partir de los informes de alta hospitalaria, sin intervención de los responsables de los correspondientes servicios asistenciales. Los casos objeto del estudio han sido todas las altas de hospitalización registradas en los centros participantes. Los episodios incluidos han sido los de enfermedad quirúrgica respiratoria (CDM4-Q) y los del servicio de Cirugía Torácica. La identificación de estos casos se realizó usando los códigos de la novena edición de la Clasificación Internacional de Enfermedades, Modificación Clínica. Para valorar las diferencias en gravedad y complejidad de los casos se ha utilizado la clasificación de los grupos relacionados por el diagnóstico refinados. Resultados: Los diversos parámetros generales estudiados (casuística, estancia media, complicaciones, readmisiones, mortalidad y actividad) han tenido una gran variabilidad entre los participantes. El análisis concreto de intervenciones (lobectomía, neumonectomía, resecciones atípicas y neumotórax), también han oscilado considerablemente. Conclusiones: Se observa, al igual que en ediciones previas, una considerable variabilidad entre los grupos participantes. Existen áreas de mejora evidentes: estandarización de los procesos de admisión, evitando ingresos urgentes y mejorando la estancia preoperatoria; agilización de las altas hospitalarias y mejora de los informes de alta, reflejando toda la actividad y las complicaciones habidas. Algunas unidades de Cirugía Torácica deben hacer una revisión profunda de sus procesos porque pueden tener algunos parámetros con una desviación excesiva de la norma. También deben mejorarse los procesos de codificación de diagnósticos y comorbilidades

Introduction: Benchmarking entails continuous comparison of efficacy and quality among products and activities, with the primary objective of achieving excellence. Objective: To analyze the results of benchmarking performed in 2013 on clinical practices undertaken in 2012 in 17 Spanish thoracic surgery units. Methods: Study data were obtained from the basic minimum data set for hospitalization, registered in 2012. Data from hospital discharge reports were submitted by the participating groups, but staff from the corresponding departments did not intervene in data collection. Study cases all involved hospital discharges recorded in the participating sites. Episodes included were respiratory surgery (Major Diagnostic Category 04, Surgery), and those of the thoracic surgery unit. Cases were labelled using codes from the International Classification of Diseases, 9th revision, Clinical Modification. The refined diagnosis-related groups classification was used to evaluate differences in severity and complexity of cases. Results: General parameters (number of cases, mean stay, complications, readmissions, mortality, and activity) varied widely among the participating groups. Specific interventions (lobectomy, pneumonectomy, atypical resections, and treatment of pneumothorax) also varied widely. Conclusions: As in previous editions, practices among participating groups varied considerably. Some areas for improvement emerge: admission processes need to be standardized to avoid urgent admissions and to improve pre-operative care; hospital discharges should be streamlined and discharge reports improved by including all procedures and complications. Some units have parameters which deviate excessively from the norm, and these sites need to review their processes in depth. Coding of diagnoses and comorbidities is another area where improvement is needed

Benchmarking in Thoracic Surgery. Third Edition.

INTRODUCTION: Benchmarking entails continuous comparison of efficacy and quality among products and activities, with the primary objective of achieving excellence. OBJECTIVE: To analyze the results of benchmarking performed in 2013 on clinical practices undertaken in 2012 in 17 Spanish thoracic surgery units. METHODS: Study data were obtained from the basic minimum data set for hospitalization, registered in 2012. Data from hospital discharge reports were submitted by the participating groups, but staff from the corresponding departments did not intervene in data collection. Study cases all involved hospital discharges recorded in the participating sites. Episodes included were respiratory surgery (Major Diagnostic Category 04, Surgery), and those of the thoracic surgery unit. Cases were labelled using codes from the International Classification of Diseases, 9th revision, Clinical Modification. The refined diagnosis-related groups classification was used to evaluate differences in severity and complexity of cases. RESULTS: General parameters (number of cases, mean stay, complications, readmissions, mortality, and activity) varied widely among the participating groups. Specific interventions (lobectomy, pneumonectomy, atypical resections, and treatment of pneumothorax) also varied widely. CONCLUSIONS: As in previous editions, practices among participating groups varied considerably. Some areas for improvement emerge: admission processes need to be standardized to avoid urgent admissions and to improve pre-operative care; hospital discharges should be streamlined and discharge reports improved by including all procedures and complications. Some units have parameters which deviate excessively from the norm, and these sites need to review their processes in depth. Coding of diagnoses and comorbidities is another area where improvement is needed.

Determining the profiles and parameters for gene amplification testing of growth factor receptors in lung cancer.

Growth factor receptors (GFRs) are amenable to therapeutic intervention in cancer and it is important to select patients appropriately. One of the mechanisms for activation of GFRs is gene amplification (GA) but discrepancies arising from the difficulties associated with data interpretation and the lack of agreed parameters confound the comparison of results from different laboratories. Here, we attempt to establish appropriate conditions for standardization of the determination of GA in a panel of GFRs. A NSCLC tissue microarray panel containing 302 samples was screened for alterations at ALK, FGFR1, FGFR2, FGFR3, ERBB2, IGF1R, KIT, MET and PDGFRA by FISH, immunostaining and/or real-time quantitative RT-PCR. Strong amplification was found for FGFR1, ERBB2, KIT/PDFGRA and MET, with frequencies ranging from 1 to 6%. Thresholds for overexpression and GA were established. Strong immunostaining was found in most tumors with ERBB2, MET and KIT amplification, although some tumors underwent strong immunostaining in the absence of GA. KIT and PDFGRA were always coamplified, but only one tumor showed PDGFRA overexpression, indicating that KIT is the main target. Amplification of FGFR1 predominated in squamous cell carcinomas, although the association with overexpression was inconclusive. Interestingly, alterations at ALK, MET, EGFR, ERBB2 and KRAS correlated with augmented levels of phospho-S6 protein, suggesting activation of the mTOR pathway, which may prove useful to pre-select tumors for testing. Overall, here, we provide with parameters for the determination of GA at ERBB2, MET, KIT and PDGFRA which could be implemented in the clinic to stratify lung cancer patients for specific treatments.

[Chest wall surgery]. / Cirugía de la pared torácica.

Despite the numerous differences among the distinct diseases of the chest wall, the surgery of this area shows certain common features. Treatment has progressively changed in the last few years due to advances in diagnostic techniques, minimally invasive procedures and reconstruction materials, and especially due to the multidisciplinary management of many diseases. Nuss' minimally invasive correction of pectus excavatum has gained devotees, although open approaches are performed with increasingly small incisions, almost comparable to the lateral incisions in Nuss' technique. Surgeons supporting the open approach also cite the evident disadvantages of the need for a steel implant for 2 or 3 years and for a second intervention to remove this implant. En-bloc resections with reconstruction using materials, which are increasingly better and covered by myocutaneous grafts in collaboration with plastic surgery departments, constitute a major advance in the treatment of chest wall tumors. Trimodal therapy for Pancoast tumors, consisting of induction chemotherapy and radiotherapy and subsequent surgical treatment of the tumor, currently provides the best results in terms of resectability and survival.

Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors.

The tumor suppressor gene, SMARCA4 (or BRG1), which encodes the ATPase component of the chromatin remodeling complex SWI/SNF, is commonly inactivated by mutations and deletions in lung cancer cell lines. However, SMARCA4 alterations appear to be rare in lung primary tumors. Ultra-deep sequencing technologies provide a promising alternative to achieve a sensitivity superior to that of current sequencing strategies. Here we used ultra-deep pyrosequencing to screen for mutations over the entire SMARCA4 coding region in 12 lung tumors without detectable BRG1 protein. While automatic-fluorescence-based sequencing detected one somatic mutation (p.K586X), the pyrosequencing revealed additional variants, thus increasing the sensitivity. One of the variants, which affected a consensus splice site, was confirmed by individual cloning of PCR products, ruling out the possibility of PCR or pyrosequencing artifacts. This mutation, confirmed to be somatic, was present at a frequency of ten percent, suggesting normal cell contamination in the tumor. Our analysis also allowed us to determine the sensitivity and to identify some limitations of the technology. In conclusion, in addition to cell lines, SMARCA4 is biallelically inactivated in a significant proportion of lung primary tumors, thereby constituting one of the most important genes contributing to the development of this type of cancer.

Gene amplification of the transcription factor DP1 and CTNND1 in human lung cancer.

The search for novel oncogenes is important because they could be the target of future specific anticancer therapies. In the present paper we report the identification of novel amplified genes in lung cancer by means of global gene expression analysis. To screen for amplicons, we aligned the gene expression data according to the position of transcripts in the human genome and searched for clusters of over-expressed genes. We found several clusters with gene over-expression, suggesting an underlying genomic amplification. FISH and microarray analysis for DNA copy number in two clusters, at chromosomes 11q12 and 13q34, confirmed the presence of amplifications spanning about 0.4 and 1 Mb for 11q12 and 13q34, respectively. Amplification at these regions each occurred at a frequency of 3%. Moreover, quantitative RT-PCR of each individual transcript within the amplicons allowed us to verify the increased in gene expression of several genes. The p120ctn and DP1 proteins, encoded by two candidate oncogenes, CTNND1 and TFDP1, at 11q12 and 13q amplicons, respectively, showed very strong immunostaining in lung tumours with gene amplification. We then focused on the 13q34 amplicon and in the TFDP1 candidate oncogene. To further determine the oncogenic properties of DP1, we searched for lung cancer cell lines carrying TFDP1 amplification. Depletion of TFDP1 expression by small interference RNA in a lung cancer cell line (HCC33) with TFDP1 amplification and protein over-expression reduced cell viability by 50%. In conclusion, we report the identification of two novel amplicons, at 13q34 and 11q12, each occurring at a frequency of 3% of non-small cell lung cancers. TFDP1, which encodes the E2F-associated transcription factor DP1 is a candidate oncogene at 13q34. The data discussed in this publication have been deposited in NCBIs Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series Accession No. GSE21168.

[Analysis of the current situation and outlook of thoracic surgery]. / Análisis de la situación actual y previsión de futuro de la especialidad de cirugía torácica.

OBJECTIVE: The objective of this descriptive study was to analyze the current situation and forecast the future requirements for specialists in thoracic surgery, taking into account the number of doctors entering and those possibly leaving this specialty. MATERIAL AND METHODS: The data for this study were taken from the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) (n=304), Thoracic Surgeons' Club (n=122), and the Spanish Council of Medical Associations (n=225). We also took into account the current number of resident surgeons (n=84). Other specialists were included who are not recorded in these databases but who are known to be practicing (n=10). The total number of practicing specialists obtained was 211. RESULTS: There are currently 52 working thoracic surgery departments and the highest number of practicing specialists was recorded in Madrid (n=44), Catalonia (n=33), and Andalusia (n=33). The forecast number of retirements (at age 65 years) and incorporations of new specialists means that there will be a surplus of 57 thoracic surgeons in the next 5 years. CONCLUSIONS: Thoracic surgery needs to limit the intake of new trainee specialists for at least the next 5 years.

Análisis de la situación actual y previsión de futuro de la especialidad de cirugía torácica / Analysis of the Current Situation and Outlook of Thoracic Surgery

Introduccióncon objeto de analizar la situación actual y realizar una previsión de futuro de las necesidades de especialistas de cirugía torácica, se ha llevado a cabo un estudio descriptivo teniendo en cuenta las incorporaciones y posibles salidas del sistema de médicos de esta especialidad.Material y métodoscomo base de datos se han tomado las de la Sociedad Española de Neumología y Cirugía Torácica (n=304), Club de Cirujanos Torácicos (n=122) y Consejo Español de Colegios de Médicos (n=225). También se ha considerado el número actual de médicos residentes (n=84). Se han añadido otros especialistas no censados en esta base de datos de los que se tiene constancia de su ejercicio (n=10). El total de especialistas en ejercicio considerados ha sido de 211.Resultadosactualmente hay 52 unidades de cirugía torácica con actividad y el mayor número de especialistas activos se registra en Madrid (n=44), Cataluña (n=33) y Andalucía (n=33). La previsión de jubilaciones (edad de 65 años) y nuevas incorporaciones de médicos especialistas hace que se prevea un excedente de cirujanos torácicos de 57 en los próximos 5 años.Conclusionesla especialidad de cirugía torácica debería moderar su oferta de formación de nuevos especialistas en los próximos 5 años como mínimo(AU)

ObjectiveThe objective of this descriptive study was to analyze the current situation and forecast the future requirements for specialists in thoracic surgery, taking into account the number of doctors entering and those possibly leaving this specialty.Material and methodsThe data for this study were taken from the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) (n=304), Thoracic Surgeons’ Club (n=122), and the Spanish Council of Medical Associations (n=225). We also took into account the current number of resident surgeons (n=84). Other specialists were included who are not recorded in these databases but who are known to be practicing (n=10). The total number of practicing specialists obtained was 211.ResultsThere are currently 52 working thoracic surgery departments and the highest number of practicing specialists was recorded in Madrid (n=44), Catalonia (n=33), and Andalusia (n=33). The forecast number of retirements (at age 65 years) and incorporations of new specialists means that there will be a surplus of 57 thoracic surgeons in the next 5 years.ConclusionsThoracic surgery needs to limit the intake of new trainee specialists for at least the next 5 years(AU)

[Guidelines for the diagnosis and treatment of spontaneous pneumothorax]. / Normativa sobre el diagnóstico y tratamiento del neumotórax espontáneo.

This is the fourth update of the guidelines for the diagnosis and treatment of pneumothorax published by the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR). Spontaneous pneumothorax, or the presence of air in the pleural space not caused by injury or medical intervention, is a significant clinical problem. We propose a method for classifying cases into 3 categories: partial, complete, and complete with total lung collapse. This classification, together with a clinical assessment, would provide sufficient information to enable physicians to decide on an approach to treatment. This update introduces simple aspiration in an outpatient setting as a treatment option that has yielded results comparable to conventional drainage in the management of uncomplicated primary spontaneous pneumothorax; this technique is not, as yet, widely used in Spain. For the definitive treatment of primary spontaneous pneumothorax, the technique most often used by thoracic surgeons is video-assisted thoracoscopic bullectomy and pleural abrasion. Hospitalization and conventional tube drainage is recommended for the treatment of secondary spontaneous pneumothorax. This update also has a new section on catamenial pneumothorax, a condition that is probably underdiagnosed. The definitive treatment for a recurring or persistent air leak is usually surgery or the application of talc through the drainage tube when surgery is contraindicated. Our aim in proposing algorithms for the management of pneumothorax in these guidelines was to provide a useful tool for clinicians involved in the diagnosis and treatment of this disease.

Normativa sobre el diagnóstico y tratamiento del neumotórax espontáneo / Guidelines for the diagnosis and treatment of spontaneous pneumothorax

Se presenta la cuarta puesta al día de la 'Normativa sobre diagnóstico y tratamiento del neumotórax', de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR). La presencia de aire dentro de la cavidad pleural de causa no traumática o iatrógena es un problema clínico relevante. Se propone un método de cuantificación del neumotórax mediante su clasificación en parcial, completo o total, que junto a la valoración clínica parece suficiente para adoptar las diversas actitudes terapéuticas. En la presente actualización se incorpora la aspiración simple ambulatoria, como método equiparable en resultados al drenaje convencional, para el tratamiento del neumotórax espontáneo primario no complicado, cuyo uso no está todavía muy extendido en España. Para el tratamiento definitivo del neumotórax espontáneo primario, la cirugía videotoracoscópica con bullectomía y abrasión pleural es la técnica más ampliamente utilizada por la mayoría de cirujanos torácicos. En el tratamiento del neumotórax espontáneo secundario se recomienda el ingreso y la colocación de drenaje torácico convencional. Se ha introducido también una referencia al neumotórax catamenial, probablemente infradiagnosticado. En caso de recidiva o fuga aérea persistente, el tratamiento definitivo suele ser el quirúrgico o el uso de talco a través del drenaje en caso de contraindicación. Los algoritmos de estrategia terapéutica aquí propuestos pretenden convertirse en una herramienta de trabajo útil para todos los implicados en el diagnóstico y tratamiento de esta enfermedad (AU)

This is the fourth update of the guidelines for the diagnosis and treatment of pneumothorax published by the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR). Spontaneous pneumothorax, or the presence of air in the pleural space not caused by injury or medical intervention, is a significant clinical problem. We propose a method for classifying cases into 3 categories: partial, complete, and complete with total lung collapse. This classification, together with a clinical assessment, would provide sufficient information to enable physicians to decide on an approach to treatment. This update introduces simple aspiration in an outpatient setting as a treatment option that has yielded results comparable to conventional drainage in the management of uncomplicated primary spontaneous pneumothorax; this technique is not, as yet, widely used in Spain. For the definitive treatment of primary spontaneous pneumothorax, the technique most often used by thoracic surgeons is video-assisted thoracoscopic bullectomy and pleural abrasion. Hospitalization and conventional tube drainage is recommended for the treatment of secondary spontaneous pneumothorax. This update also has a new section on catamenial pneumothorax, a condition that is probably underdiagnosed. The definitive treatment for a recurring or persistent air leak is usually surgery or the application of talc through the drainage tube when surgery is contraindicated. Our aim in proposing algorithms for the management of pneumothorax in these guidelines was to provide a useful tool for clinicians involved in the diagnosis and treatment of this disease (AU)

Cancer-associated differences in acetylcholinesterase activity in bronchial aspirates from patients with lung cancer.

In non-neuronal contexts, ACh (acetylcholine) is thought to be involved in the regulation of vital cell functions, such as proliferation, differentiation, apoptosis and cell-cell interaction. In airways, most cells express the non-neuronal cholinergic system, each containing a specific set of components required for synthesis, signal transduction and ACh hydrolysis. The aim of the present study was determine the expression of cholinergic system components in bronchial aspirates from control subjects and patients with lung cancer. We conducted an analysis of cholinergic components in the stored soluble and cellular fraction of bronchial aspirates from non-cancerous patients and patients diagnosed with lung cancer. The results show that the fluid secreted by human lung cells contains enough AChE (acetylcholinesterase) activity to control ACh levels. Thus these findings demonstrate that: (i) AChE activity is significantly lower in aspirates from squamous cell carcinomas; (ii) the molecular distribution of AChE in both bronchial cells and fluids consisted of amphiphilic monomers and dimers; and (iii) choline acetyltransferase, nicotinic receptors and cholinesterases are expressed in cultured human lung cells, as demonstrated by RT-PCR (reverse transcriptase-PCR). It appears that the non-neuronal cholinergic system is involved in lung physiology and lung cancer. The physiological consequences of the presence of non-neuronal ACh will depend on the particular cholinergic signalling network in each cell type. Clarifying the pathophysiological actions of ACh remains an essential task and warrants further investigation.

Prognostic significance of synaptophysin in stage I of squamous carcinoma and adenocarcinoma of the lung.

BACKGROUND: The prognostic significance of the presence of a neuroendocrine marker (synaptophysin, SY) was analyzed in stage I of squamous carcinoma and adenocarcinoma of the lung. METHODS: A multicentric retrospective study was conducted with immunohistochemical staining in a single center of 318 patients resected for squamous carcinoma or adenocarcinoma in pathologic stage I. RESULTS: In all, 162 cases of squamous carcinoma and 156 cases of adenocarcinoma were identified, which included 105 patients in stage IA (50 patients with squamous carcinoma and 55 patients with adenocarcinoma) and 213 in stage IB (112 with squamous carcinoma and 101 with adenocarcinoma). Eighty-six tumors showed a presence of SY+ (27%). Univariate analysis showed lower survival rates at 5 years for those patients older than 70 years of age compared with those patients younger than 70 years of age (60.35% vs 70.57%; P = .007) and for those patients with SY+ compared with those with SY- (52.48% vs 72.68%; P = .0017). Patients with SY+ tumors showed a higher rate of recurrence than patients with SY- tumors (50% vs 33.6%; P = .008). Multivariate analysis showed that those patients greater that 70 years of age (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.14-2.65) and the presence of SY (HR, 2.15; 95% CI, 1.40-3.30) were significant independent prognostic factors associated with a poor outcome. CONCLUSIONS: Stage I of squamous carcinoma and adenocarcinoma of the lung with SY+ has a poor prognosis, with a higher frequency of recurrence and lower survival rates.

Wnt signaling promoter hypermethylation distinguishes lung primary adenocarcinomas from colorectal metastasis to the lung.

Promoter hypermethylation is responsible for gene inactivation during carcinogenesis. It has been proposed that there is some degree of specificity in the set of genes that become altered by this mechanism in distinct tumor types. To understand whether promoter hypermethylation may differentiate the site of origin, 49 lung adenocarcinomas from 31 lung primaries and 18 metastases from colorectal primaries, respectively, were tested for the presence of this alteration in the APC, CDH1, DAPK, GSTP1, MLH1, MGMT, P14, P16, RARbeta2, RASSF1, sFRP1 and WIF-1 genes. A distinct profile was apparent for the 2 groups of lung tumors and the frequencies of promoter hypermethylation at sFRP1 and WIF-1, 2 genes involved in Wnt signaling, and at CDH1 were significantly higher in colorectal metastases than in lung primaries, whereas methylation of the APC promoter was significantly more common in lung primary adenocarcinomas. Some tumors showed concomitant APC, sFRP1 and WIF-1 gene inactivation, indicating that multiple DNA methylation events must have occurred to definitively down-regulate the signaling through Wnt. However, promoter hypermethylation at the APC and CDH1 genes tended to be mutually exclusive (Fisher's exact test, p = 0.006), suggesting a similar role in carcinogenesis. In conclusion, we propose that inactivation by promoter hypermethylation at the APC, CDH1, sFRP1 and WIF-1 genes may contribute to the discrimination of lung primary adenocarcinomas from colorectal metastasis to the lung, and report the simultaneous presence of methylation at the promoters of multiple genes involved in the Wnt signaling. This may have biological consequences for carcinogenesis.

Molecular context of the EGFR mutations: evidence for the activation of mTOR/S6K signaling.

PURPOSE: Activating somatic mutations in the epidermal growth factor receptor (EGFR) gene are present in a small subset of lung adenocarcinomas. These mutations cluster in specific regions and confer sensitivity to inhibitors of the tyrosine kinase activity of EGFR. To further determine the genetic and molecular characteristics of tumors carrying EGFR gene mutations, we investigated the EGFR gene status in lung adenocarcinomas and evaluated its association with specific characteristics of the patients and tumors, such as mutations at KRAS and p53, EGFR and ErbB2 gene amplification, levels of EGFR and HER2 proteins, and levels of downstream effectors of EGFR, such as phospho-extracellular signal-regulated kinase and phospho-S6 proteins. EXPERIMENTAL DESIGN: The mutational status of EGFR was determined by direct sequencing in 86 primary lung adenocarcinomas and 12 lung cancer cell lines, and was correlated with a number of variables relating to the tumor and patient. A tissue microarray containing 37 lung tumors was constructed to determine, by fluorescence in situ hybridization analysis, the number of copies of EGFR and ErbB2 genes and, by immunohistochemistry, the levels of EGFR, HER2, phospho-ERK, and phospho-S6 proteins. RESULTS: EGFR gene mutations were identified in 13% of the primary tumors. The type and clustering of the mutations were identical to those previously reported. Amplification of the EGFR occurred in 14% of the tumors and could arise in tumors with EGFR mutations. Interestingly, mTOR activation, as measured indirectly by augmented levels of phospho-S6 protein, was more frequent in tumors with gene alterations in either EGFR or KRAS (P = 0.00005; Fisher's exact test) than in their wild-type counterparts. CONCLUSIONS: Our data agree with the accumulation of EGFR mutations in a subset of patients with lung cancer. Moreover, we report EGFR gene amplification in EGFR-mutant tumors and a positive correlation between EGFR or KRAS alterations and activation of mTOR signaling.

Cholinesterase activity of human lung tumours varies according to their histological classification.

The probable involvement of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in cancer and the relevance of cholinergic responses for lung cancer growth prompted us to study whether cholinesterase activity of human lung is altered by malignancy. Surgical pieces of non-small lung carcinomas (NSLC) and their adjacent non-cancerous tissues (ANCT) were analysed for AChE and BChE activities. AChE activity in adenocarcinoma (AC) was 7.80 +/- 5.59 nmol of substrate hydrolysed per min and per mg of protein (mU/mg), the same as in their ANCT (8.83 +/- 4.72 mU/mg; P = 0.823); in large cell carcinoma (LCC), 7.52 +/- 3.32 mU/mg, approximately 50% less than in their ANCT (15.39 +/- 5.66 mU/mg; P = 0.043); and in squamous cell carcinoma (SCC), 1.39 +/- 0.58 mU/mg, 80% less than in ANCT (6.08 +/- 2.88 mU/mg; P = 0.003). BChE activity was 5.85 +/- 3.20 mU/mg in AC and 9.56 +/- 3.38 mU/mg in ANCT (P = 0.022); 2.94 +/- 2.01 mU/mg in LCC and 6.50 +/- 6.63 mU/mg in ANCT (P = 0.068); and 4.49 +/- 2.30 mU/mg in SCC and ANCT 6.56 +/- 4.09 mU/mg (P = 0.026). Abundant AChE dimers and fewer monomers were identified in lung and, although their distribution was unaffected by cancer, the binding with concanavalin A revealed changes in AChE glycosylation between SCC and their ANCT. The fall in BChE activity affected all molecules, with a strong decrease of the amphiphilic tetramers. Western blotting revealed protein bands with the expected mass of the principal AChE subunits, and the deeper intensity of the protein signal in SCC than in healthy lung, in lanes loaded with the same units of AChE activity, supported an augment in the amount of AChE protein/unit of AChE activity in SCC. The increased availability of acetylcholine in neoplastic lung, resulting from the fall of cholinesterase activity, may enhance cholinergic signalling and contribute to tumour progression.

Resultados clinicofuncionales de la cirugía en las bullas gigantes de pulmón / Clinical functional results of lung giant bullas surgery

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