Aberrant TIMP-1 production in tumor-associated fibroblasts drives the selective benefits of nintedanib in lung adenocarcinoma.

The fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor-associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified. Here we examined the role of tissue inhibitor of metalloproteinase-1 (TIMP-1), a tumor-promoting cytokine overproduced in ADC-TAFs. To this aim, we combined genetic approaches with in vitro and in vivo preclinical models based on patient-derived TAFs. Nintedanib reduced TIMP-1 production more efficiently in ADC-TAFs than SCC-TAFs through a SMAD3-dependent mechanism. Cell culture experiments indicated that silencing TIMP1 in ADC-TAFs abolished the therapeutic effects of nintedanib on cancer cell growth and invasion, which were otherwise enhanced by the TAF secretome. Consistently, co-injecting ADC cells with TIMP1-knockdown ADC-TAFs into immunocompromised mice elicited a less effective reduction of tumor growth and invasion under nintedanib treatment compared to tumors bearing unmodified fibroblasts. Our results unveil a key mechanism underlying the selective mode of action of nintedanib in ADC based on the excessive production of TIMP-1 in ADC-TAFs. We further pinpoint reduced SMAD3 expression and consequent limited TIMP-1 production in SCC-TAFs as key for the resistance of SCC to nintedanib. These observations strongly support the emerging role of TIMP-1 as a critical regulator of therapy response in solid tumors.

Morphological Characterization of Human Lung Cancer Organoids Cultured in Type I Collagen Hydrogels: A Histological Approach.

The malignity of lung cancer is conditioned by the tumor microenvironment (TME), in which cancer-associated fibroblasts (CAFs) are relevant. In this work, we generated organoids by combining A549 cells with CAFs and normal fibroblasts (NF) isolated from adenocarcinoma tumors. We optimized the conditions for their manufacture in a short time. We evaluated the morphology of organoids using confocal microscopy analysis of F-actin, vimentin and pankeratin. We determined the ultrastructure of the cells in the organoids via transmission electron microscopy and the expression of CDH1, CDH2 and VIM via RT-PCR. The addition of stromal cells induces the self-organization of the organoids, which acquired a bowl morphology, as well as their growth and the generation of cell processes. They also influenced the expression of genes related to epithelial mesenchymal transition (EMT). CAFs potentiated these changes. All cells acquired a characteristic secretory phenotype, with cohesive cells appearing inside the organoids. In the periphery, many cells acquired a migratory phenotype, especially in organoids that incorporated CAFs. The deposit of abundant extracellular matrix could also be observed. The results presented here reinforce the role of CAFs in the progression of lung tumors and could lay the foundation for a useful in vitro pharmacological model.

In Vitro Effect of Δ9-Tetrahydrocannabinol and Cannabidiol on Cancer-Associated Fibroblasts Isolated from Lung Cancer.

There is evidence that demonstrates the effect of cannabinoid agonists inhibiting relevant aspects in lung cancer, such as proliferation or epithelial-to-mesenchymal transition (EMT). Most of these studies are based on evidence observed in in vitro models developed on cancer cell lines. These studies do not consider the complexity of the tumor microenvironment (TME). One of the main components of the TME is cancer-associated fibroblasts (CAFs), cells that are relevant in the control of proliferation and metastasis in lung cancer. In this work, we evaluated the direct effects of two cannabinoid agonists, tetrahydrocannabinol (THC) and cannabidiol (CBD), used alone or in combination, on CAFs and non-tumor normal fibroblasts (NFs) isolated from adenocarcinoma or from healthy lung tissue from the same patients. We observed that these compounds decrease cell density in vitro and inhibit the increase in the relative expression of type 1 collagen (COL1A1) and fibroblast-specific protein 1 (FSP1) induced by transforming growth factor beta (TGFß). On the other hand, we studied whether THC and CBD could modulate the interactions between CAFs or NFs and cancer cells. We conditioned the culture medium with stromal cells treated or not with THC and/or CBD and cultured A549 cells with them. We found that culture media conditioned with CAFs or NFs increased cell density, induced morphological changes consistent with EMT, inhibited cadherin-1 (CDH1) gene expression, and induced an increase in the relative expression of cadherin-2 (CDH2) and vimentin (VIM) genes in A549 cells. These changes were inhibited or decreased by THC and CBD administered alone or in combination. In another series of experiments, we conditioned culture media with A549 cells treated or not with THC and/or CBD, in the presence or absence of TGFß. We observed that culture media conditioned with A549 in the presence of TGFß induced an increase in the expression of COL1A1 and VIM, both in CAFs and in non-tumor NFs. Both THC and CBD ameliorated these effects. In summary, the results presented here reinforce the usefulness of cannabinoid agonists for the treatment of some relevant aspects of lung cancer pathology, and demonstrate in a novel way their possible effects on CAFs as a result of their relationship with cancer cells. Likewise, the results reinforce the usefulness of the combined use of THC and CBD, which has important advantages in relation to the possibility of using lower doses, thus minimizing the psychoactive effects of THC.

Cannabinoid receptor expression in non-small cell lung cancer. Effectiveness of tetrahydrocannabinol and cannabidiol inhibiting cell proliferation and epithelial-mesenchymal transition in vitro.

BACKGROUND/OBJECTIVE: Patients with non-small cell lung cancer (NSCLC) develop resistance to antitumor agents by mechanisms that involve the epithelial-to-mesenchymal transition (EMT). This necessitates the development of new complementary drugs, e.g., cannabinoid receptors (CB1 and CB2) agonists including tetrahydrocannabinol (THC) and cannabidiol (CBD). The combined use of THC and CBD confers greater benefits, as CBD enhances the effects of THC and reduces its psychotropic activity. We assessed the relationship between the expression levels of CB1 and CB2 to the clinical features of a cohort of patients with NSCLC, and the effect of THC and CBD (individually and in combination) on proliferation, EMT and migration in vitro in A549, H460 and H1792 lung cancer cell lines. METHODS: Expression levels of CB1, CB2, EGFR, CDH1, CDH2 and VIM were evaluated by quantitative reverse transcription-polymerase chain reaction. THC and CBD (10-100 µM), individually or in combination (1:1 ratio), were used for in vitro assays. Cell proliferation was determined by BrdU incorporation assay. Morphological changes in the cells were visualized by phase-contrast and fluorescence microscopy. Migration was studied by scratch recolonization induced by 20 ng/ml epidermal growth factor (EGF). RESULTS: The tumor samples were classified according to the level of expression of CB1, CB2, or both. Patients with high expression levels of CB1, CB2, and CB1/CB2 showed increased survival reaching significance for CB1 and CB1/CB2 (p = 0.035 and 0.025, respectively). Both cannabinoid agonists inhibited the proliferation and expression of EGFR in lung cancer cells, and CBD potentiated the effect of THC. THC and CBD alone or in combination restored the epithelial phenotype, as evidenced by increased expression of CDH1 and reduced expression of CDH2 and VIM, as well as by fluorescence analysis of cellular cytoskeleton. Finally, both cannabinoids reduced the in vitro migration of the three lung cancer cells lines used. CONCLUSIONS: The expression levels of CB1 and CB2 have a potential use as markers of survival in patients with NSCLC. THC and CBD inhibited the proliferation and expression of EGFR in the lung cancer cells studied. Finally, the THC/CBD combination restored the epithelial phenotype in vitro.

Genomic Profiling of Patient-Derived Xenografts for Lung Cancer Identifies B2M Inactivation Impairing Immunorecognition.

Purpose: We aimed to maximize the performance of detecting genetic alterations in lung cancer using high-throughput sequencing for patient-derived xenografts (PDXs).Experimental Design: We undertook an integrated RNA and whole-exome sequencing of 14 PDXs. We focused on the genetic and functional analysis of ß2-microglobulin (B2M), a component of the HLA class-I complex.Results: We identified alterations in genes involved in various functions, such as B2M involved in immunosurveillance. We extended the mutational analysis of B2M to about 230 lung cancers. Five percent of the lung cancers carried somatic mutations, most of which impaired the correct formation of the HLA-I complex. We also report that genes such as CALR, PDIA3, and TAP1, which are involved in the maturation of the HLA-I complex, are altered in lung cancer. By gene expression microarrays, we observed that restitution of B2M in lung cancer cells upregulated targets of IFNα/IFNγ. Furthermore, one third of the lung cancers lacked the HLA-I complex, which was associated with lower cytotoxic CD8+ lymphocyte infiltration. The levels of B2M and HLA-I proteins correlated with those of PD-L1. Finally, a deficiency in HLA-I complex and CD8+ infiltration tended to correlate with reduced survival of patients with lung cancer treated with anti-PD-1/anti-PD-L1.Conclusions: Here, we report recurrent inactivation of B2M in lung cancer. These observations, coupled with the mutations found at CALR, PDIA3, and TAP1, and the downregulation of the HLA-I complex, indicate that an abnormal immunosurveillance axis contributes to lung cancer development. Finally, our observations suggest that an impaired HLA-I complex affects the response to anti-PD-1/anti-PD-L1 therapies. Clin Cancer Res; 23(12); 3203-13. ©2016 AACR.

Video-assisted thoracic surgery and anatomical lung resections. Where do we stand? National survey by the Spanish Society of Thoracic Surgery. / Cirugía torácica video-asistida y resecciones pulmonares anatómicas. ¿Dónde estamos? Encuesta nacional de la Sociedad Española de Cirugía Torácica.

INTRODUCTION: The objective of this survey is to find out the cumulated experience and the current situation of video-assisted thoracic surgery (VATS) for anatomical lung resections in Spain. METHODS: This is a descriptive study performed from two independent surveys designed through the Survey Monkey® web platform. The first survey was aimed at 53 thoracic surgery departments from the public and state-assisted national health system. The second survey, of a personal nature, was directed at 315 thoracic surgeons in active service, including physicians at their residency program. The surveys were kept operative from 18/11/2014 to 15/01/2015. RESULTS: The first survey was answered by 32 (60%) departments and the second by 167 (53%) professionals. A total of 29 (91%) of the thoracic surgery departments represented recognized having some level of experience in this technique. However, a great proportion of departments, 15 (52%), counted less than 100 procedures and the cumulated time of experience was lower than 5 years in 19 (66%) departments. Among all the individual respondents, 126 (77%) admitted having performed the procedure at some point. Of those without any experience, at least 36 (95%) of them recognized that future training in this technique is one of their future professional objectives. CONCLUSIONS: Waiting for future prospective national registries contribute further information about the expansion of this technique in our country, the results of the current survey show, up to now, the best reflection of clinical practice and opinion of the surgeons involved in the development of VATS.

Cirugía torácica video-asistida y resecciones pulmonares anatómicas. ¿Dónde estamos? Encuesta nacional de la Sociedad Española de Cirugía Torácica / Video-assisted thoracic surgery and anatomical lung resections. Where do we stand? National survey by the Spanish Society of Thoracic Surgery

INTRODUCCIÓN: El objetivo de esta encuesta es conocer la experiencia acumulada y situación actual de la cirugía torácica video-asistida (VATS) aplicada a las resecciones pulmonares anatómicas en España. MÉTODOS: Se realizó un estudio descriptivo a partir de 2 encuestas independientes a través de la plataforma Survey Monkey (R). La primera encuesta se dirigió a 53 servicios de cirugía torácica de la red sanitaria pública y/o concertada nacional. La segunda encuesta, de carácter personal, se destinó a 315 cirujanos torácicos en activo, incluyendo médicos residentes. Las encuestas permanecieron activas desde el 18 de noviembre del 2014 hasta el 15 de enero del 2015. RESULTADOS: La primera encuesta fue contestada por 32 (60%) servicios y la segunda por 167 (53%) profesionales. Un total de 29 (91%) de los servicios que colaboraron, reconocieron tener algún tipo de experiencia en esta técnica. Sin embargo, la mayor parte de los mismos, 15 (52%), habían realizado menos de 100 procedimientos y el tiempo de experiencia acumulado fue inferior de 5 años en 19 (66%) servicios. Del total de encuestados de forma personal, 126 (77%) admitieron haber realizado esta técnica en alguna ocasión. De aquellos sin ninguna experiencia, al menos 36 (95%) reconocieron que la formación en esta técnica quirúrgica es uno de sus próximos objetivos profesionales. CONCLUSIONES: En espera de que futuros registros prospectivos nos aporten más información sobre la expansión de esta técnica en nuestro país, los resultados de la actual encuesta representan el mejor reflejo de la práctica clínica y opinión de los cirujanos implicados en el desarrollo de la VATS

INTRODUCTION: The objective of this survey is to find out the cumulated experience and the current situation of video-assisted thoracic surgery (VATS) for anatomical lung resections in Spain. METHODS: This is a descriptive study performed from two independent surveys designed through the Survey Monkey(R) web platform. The first survey was aimed at 53 thoracic surgery departments from the public and state-assisted national health system. The second survey, of a personal nature, was directed at 315 thoracic surgeons in active service, including physicians at their residency program. The surveys were kept operative from 18/11/2014 to 15/01/2015. RESULTS: The first survey was answered by 32 (60%) departments and the second by 167 (53%) professionals. A total of 29 (91%) of the thoracic surgery departments represented recognized having some level of experience in this technique. However, a great proportion of departments, 15 (52%), counted less than 100 procedures and the cumulated time of experience was lower than 5 years in 19 (66%) departments. Among all the individual respondents, 126 (77%) admitted having performed the procedure at some point. Of those without any experience, at least 36 (95%) of them recognized that future training in this technique is one of their future professional objectives. CONCLUSIONS: Waiting for future prospective national registries contribute further information about the expansion of this technique in our country, the results of the current survey show, up to now, the best reflection of clinical practice and opinion of the surgeons involved in the development of VATS

Association of PD-1, PD-L1, and CTLA-4 Gene Expression and Clinicopathologic Characteristics in Patients With Non-Small-Cell Lung Cancer.

INTRODUCTION: Recent studies show a potential benefit of therapies that target programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitory checkpoints in a subgroup of patients with non-small-cell lung cancer (NSCLC), without the clinicopathologic characteristics related to positive responses to these treatments being well determined. The aim of this study was to determine PD-1, PD-L1, and CTLA-4 gene expression at the mRNA level in tumoral tissue from patients with NSCLC and analyze their possible relationship with the clinicopathological characteristics and their potential prognostic role. PATIENTS AND METHODS: PD-1, PD-L1, and CTLA-4 expression levels were analyzed using real-time quantitative reverse transcriptase polymerase chain reaction in fresh-frozen tumor and normal adjacent lung tissue samples from 78 patients with NSCLC. Later, a significant association between mRNA levels, clinicopathologic characteristics, and patient's survival was assessed. RESULTS: No significant correlation between gene expression levels and sex, age, histological type, smoking status, pathologic stage, or tumor differentiation was found. However, higher levels of PD-1 were significantly associated with worse prognosis in patients with NSCLC, and PD-L1 overexpression was associated with a worse prognosis in stage I patients and in Grade 1 to 2 tumors. CONCLUSION: Alterations in PD-1/PD-L1 and CTLA-4 expression in lung tumoral tissue seem not to be related to age, sex, smoking status, histological type, pathological stage, or tumor differentiation degree. However, PD-1 and PD-L1 overexpression might predict worse survival in patients with stage I NSCLC and in well differentiated tumors.

Abordajes anteriores mini-open en el raquis toracolumbar / Mini-open approaches in anterior lumbar spine surgery

Introducción El abordaje anterior vertebral conocido como mini-open fue introducido hace unos años para el tratamiento quirúrgico de la patología del raquis. Dicho abordaje permite la exposición directa de las estructuras anteriores, cuerpo y disco intervertebral, la descompresión anterior del saco dural y la reconstrucción y/o estabilización de los niveles de interés con un sistema adecuado. En el presente trabajo presentamos nuestra experiencia en mini-open anterior spine surgery (MOASS) en el abordaje anterior del raquis para tratamiento de patología del raquis toracolumbar. Material y métodos En el periodo entre enero de 2004 y julio de 2011 hemos realizado 74 abordajes anteriores de columna mediante cirugía abierta. En 38 casos utilizamos la técnica MOASS a distintos niveles: torácico, lumbar e infraumbilical extraperitoneal. Resultados No tuvimos mortalidad quirúrgica ni postoperatoria, ni déficits neurológicos añadidos derivados del acto quirúrgico, en ninguna de las técnicas (clásica versus MOASS). Las complicaciones fueron escasas y corregidas con el adecuado tratamiento. Conclusiones Mediante la técnica MOASS hemos realizado la corrección quirúrgica de lesiones vertebrales que pueden afectar al raquis toracolumbar, con resultados similares a los obtenidos mediante el abordaje clásico y ventajas reseñables (AU)

Introduction The anterior spine approach known as «mini-open» was introduced a few years ago for the surgical treatment of spine diseases. This approach allows the anterior, body and intervertebral disc structures to be exposed, as well as the anterior compression of the dural sac and the reconstruction and/or stabilisation of the levels of interest with an appropriate system. In the present article we present our experience in mini-open anterior spine surgery (MOASS) approach in the treatment of lumbar spine diseases. Material and methods We performed 74 anterior spine approaches using open surgery between the period January 2004 and July 2011. In 38 cases we used the MOASS technique at different levels: thoracic, lumbar, and infraumbilical extraperitoneal. Results There were no surgical or post-operative deaths, or further neurological deficits arising from the surgical procedure in any of the techniques (classic versus MOASS). The few complications were corrected with the appropriate treatment. Conclusions Using the MOASS technique we have performed corrective surgery on spine injuries that could affect the thoracic spinal column, with similar results to those obtained using the classic approach and with obvious advantages (AU)

[Mini-open approaches in anterior lumbar spine surgery]. / Abordajes anteriores mini-open en el raquis toracolumbar.

INTRODUCTION: The anterior spine approach known as «mini-open¼ was introduced a few years ago for the surgical treatment of spine diseases. This approach allows the anterior, body and intervertebral disc structures to be exposed, as well as the anterior compression of the dural sac and the reconstruction and/or stabilisation of the levels of interest with an appropriate system. In the present article we present our experience in mini-open anterior spine surgery (MOASS) approach in the treatment of lumbar spine diseases. MATERIAL AND METHODS: We performed 74 anterior spine approaches using open surgery between the period January 2004 and July 2011. In 38 cases we used the MOASS technique at different levels: thoracic, lumbar, and infraumbilical extraperitoneal. RESULTS: There were no surgical or post-operative deaths, or further neurological deficits arising from the surgical procedure in any of the techniques (classic versus MOASS). The few complications were corrected with the appropriate treatment. CONCLUSIONS: Using the MOASS technique we have performed corrective surgery on spine injuries that could affect the thoracic spinal column, with similar results to those obtained using the classic approach and with obvious advantages.

Circulating DNA is a useful prognostic factor in patients with advanced non-small cell lung cancer.

BACKGROUND: Circulating DNA is observed at higher concentrations in patients with lung cancer than in controls. Qualitative and quantitative analysis of circulating DNA is a promising noninvasive tool. Our aim was to prospectively study the association between the catalytic subunit of telomerase (human telomerase reverse transcriptase [hTERT]) in plasma and clinical variables and survival in a large-scale non-small cell lung cancer (NSCLC) study. METHODS: Four hundred forty-six patients with stages IIIB and IV NSCLC with a median follow-up of 9.7 months (range, 0.5-45) were analyzed. Blood samples were collected before therapy start (cisplatin/docetaxel). Quantification of baseline circulating DNA was determined as the amount of free hTERT in plasma, by using real-time quantitative polymerase chain reaction. RESULTS: Patients with hTERT ≤ 49.8 ng/ml (median value) had a median time to progression (TTP) of 6.3 months compared with 4.9 for hTERT more than 49.8 ng/ml (p = 0.001). Overall survival (OS) was significantly higher (10.9 versus 9.3 months) at lower hTERT levels (p = 0.012). When calculations were done using hTERT as continuous variable, we did not observe independent significant differences. Thus, there is an apparent discrepancy in p values when hTERT is considered as a continuous versus dichotomized variable. There was a tendency to differentiate median hTERT levels with respect to response rates (complete response + partial response: 33.1 versus stable disease + progressive disease: 50.7 ng/ml, p = 0.12), but other clinical variables such as age, gender, performance status, stage, histology, and number of metastatic locations were not associated with hTERT. In multivariate analysis, hTERT was an independent prognostic variable for both TTP (hazard ratio: 1.44, p < 0.001) and OS (hazard ratio: 1.33, p = 0.007). CONCLUSIONS: In advanced NSCLC, high pretreatment circulating hTERT level is an independent poor prognostic marker for TTP and OS. Circulating DNA is a noninvasive marker, which may help to improve the prognostic profile of these patients.

Clinical-therapeutic management of thoracoscopy in pleural effusion: a groundbreaking technique in the twenty-first century.

INTRODUCTION: The aim of this study was to investigate the effectiveness of thoracoscopy in the diagnosis of non-affiliated pleural effusions (PE). MATERIAL AND METHODS: A five-year prospective study including data from 110 patients that were clinically diagnosed as benign (14.5%), malign (34.5%) and non-affiliated (50.9%). PE in patents without oncology disease and negative biopsy or cytology were considered as benign. Malignant diagnosis was established according to a pleural biopsy, compatible cytology and/or clinical features. Remaining cases were considered as non-affiliated. Thoracoscopy was done under local anaesthesia and sedation. RESULTS: Thoracoscopy confirmed previous clinical diagnosis of benignity and malignity. Regarding non-affiliated patients, 30.35% were diagnosed after thoracoscopy as unspecific pleuritis, 17.86% mesothelioma and 1.79% pleural tuberculosis (TBC). The other 48.21% of patients reported as non-affiliated were diagnosed with pleural carcinoma. Statistical analysis did not reveal differences between frequencies analysed. CONCLUSIONS: Our results indicate that thoracoscopy is a cost-effective and reliable technique for obtaining histological diagnosis in PE and also allows a directed pleurodesis if indicated.

Efficacy of moxonidine in the treatment of hypertension in obese, noncontrolled hypertensive patients.

BACKGROUND: Obesity has become an epidemic problem, contributing to metabolic syndrome, type 2 diabetes, hypertension, and cardiovascular disease. An adequate blood pressure control in this population of obese individuals is extremely difficult to achieve, and in most cases, therapeutic combinations are required. Pharmacologic treatment with moxonidine, a central I(1) imidazole receptor agonist, is a very interesting option because it acts upon the mechanisms implicated in the development of arterial hypertension in these patients. In addition, the drug improves the peripheral insulin resistance often found in obese patents, which contributes to maintain high blood pressure. METHODS: An interventional study has been designed, adding moxonidine to noncontrolled hypertensive, obese subjects in whom a hypocaloric diet was previously recommended. A total of 25 primary care centers participated in the study, with a total of 135 patients recruited. RESULTS: One hundred twelve patients were included in the study; 25 of them had type 2 diabetes. The mean reduction in systolic and diastolic blood pressure after 6 months treatment with moxonidine was 23.0 and 12.9 mm Hg, respectively. The mean systolic and diastolic pressures were 158.5 +/- 10.6 and 95.1 +/- 9 mm Hg, respectively, at baseline, versus 135.5 +/- 11.6 and 82.2 +/- 5.8 mm Hg at the end of the study. Creatinine clearance was significantly decreased in hyperfiltrating obese patients (143.6 +/- 31 vs. 128.2 +/- 27.9, P < 0.0001), without any significant change in patients with normal or slightly decreased renal function (81.9 +/- 18.9 vs. 80.9 +/- 17.5). Only 8 mild adverse reactions in 7 patients were recorded during the study. CONCLUSION: Moxonidine is useful and safe for controlling arterial hypertension in obese patients.

Tratamiento quirúrgico de los tumores neuroendocrinos de localización broncopulmonar / Surgical treatment of bronchopulmonary neuroendocrine tumors

Introducción: El objetivo de este trabajo es revisar nuestra experiencia con los tumores neuroendocrinos de localización broncopulmonar, en especial el tipo de tratamiento quirúrgico aplicado en función del tipo histológico. Material y métodos: Hemos realizado un estudio retrospectivo sobre 45 pacientes: 35 casos de carcinoides típicos, 6 de carcinoides atípicos, 1 oat cell y 3 de carcinomas de células grandes. Los tumores fueron clasificados siguiendo los criterios de Travis. Resultados: El tratamiento quirúrgico practicado fue: 4 neumonectomías, 23 lobectomías, 6 bilobectomías, 3 resecciones atípicas por videocirugía, 7 broncoplastias con lobectomía y 2 broncoplastias sin resección pulmonar. En el 86 por ciento de los casos el estadio fue tipo I (9 IA y 30 IB), clasificándose 5 pacientes como IIIA, y 1 como IIIB. El estudio rutinario de los pacientes incluyó: radiología de tórax, analítica completa, tomografía computarizada toracoabdominal y broncoscopia. El seguimiento medio ha sido de 46,09 meses. Conclusiones: La gran mayoría de tumores neuroendocrinos tratables con cirugía son de bajo grado de agresividad (carcinoides típicos). El tratamiento quirúrgico también es el de elección en la mayoría de los carcinoides atípicos, aunque en éstos el grado de agresividad es mayor, al provocar diseminación ganglionar locorregional o metástasis en mayor proporción que los anteriores. En los carcinomas de célula grande con diferenciación neuroendocrina y en los cacinomas de células pequeñas, el tratamiento óptimo no está bien definido, aunque la cirugía parece ser una opción que debe plantearse siempre que sea posible, combinada o no con otras terapias (AU)