Pre-existing tumor host immunity characterization in resected non-small cell lung cancer.

INTRODUCTION: Neoadjuvant and adjuvant immune checkpoint blockade (ICB) have recently become standard of care in resectable non-small cell lung cancer (NSCLC). Yet, biomarkers that inform patients who benefit from this approach remain largely unknown. Here, we interrogated the tumor immune microenvironment (TIME) in early-stage NSCLC patients that underwent up-front surgery. METHODS: A total of 185 treatment-naïve patients with early-stage NSCLC, that underwent up-front surgical treatment between 2006 and 2018 at Hospital del Mar were included. 124 lung adenocarcinomas (LUADs), and 61 squamous cell carcinoma (LUSCs) were included in a tissue microarray. Immunohistochemistry for CD3, CD4, CD8, CD68, CD80, CD103, FOXP3, PD-1, PD-L1, PD-L2 and HLA class II were evaluated by digital image analysis (QuPath software). TIME was categorized into four groups using PD-L1 expression in tumor cells (<1 % or ≥1 %) and tumor resident memory (CD103+) immune cells (using the median as cut-off). We explored the association between different TIME dimensions and patient's clinicopathological features and outcomes. RESULTS: We found increased levels of T cell markers (CD3+, CD4+, CD8+ cells), functional immune markers (FOXP3+ cells) as well as, higher HLA-II tumor membrane expression in LUADs compared to LUSCs (p < 0.05 for all). In contrast, LUSCs displayed higher percentage of intratumor macrophages (CD68+ cells) as well as, higher PD-L1 and PD-L2 tumor membrane expression (p < 0.05 for all). Unsupervised analysis revealed three different tumor subsets characterized by membrane tumor expression of PD-L1, PD-L2 and HLA-class II. Enrichment of T cells (CD3+, CD8+ cells), regulatory T cells (FOXP3+ cells) and macrophages (CD68+ cells) was observed in the CD103+/PD-L1+ group (p < 0.05 for all). Multivariate analysis showed that infiltration by CD103+ immune cells was associated with improved OS (p = 0.009). CONCLUSIONS: TIME analysis in resected NSCLC highlighted differences by histology, PD-L1 expression and molecular subgroups. Biomarker studies using IHC might aid to individually tailor adjuvant treatment in early-stage NSCLC.

Association between histological diaphragm atrophy and ultrasound diaphragm expiratory thickness in ventilated patients.

BACKGROUND: Diaphragm fiber atrophy has been evidenced after short periods of mechanical ventilation (MV) and related to critical illness-associated diaphragm weakness. Atrophy is described as a decrease in diaphragm fiber cross-sectional area (CSA) in human diaphragm biopsy, but human samples are still difficult to obtain in clinics. In recent years, ultrasound has become a useful tool in intensive care to evaluate diaphragm anatomy. The present study aimed to evaluate the ability of diaphragm expiratory thickness (Tdi) measured by ultrasound to predict diaphragm atrophy, defined by a decrease in diaphragm fiber CSA obtained through diaphragm biopsy (the gold standard technique) in ventilated patients. METHODS: Diaphragm biopsies and diaphragm ultrasound were performed in ventilated donors and in control subjects. Demographic variables, comorbidities, severity on admission, treatment, laboratory test results and evolution variables were evaluated. Immunohistochemical analysis to determine CSA and ultrasound measurements of Tdi at end-expiration were performed, and median values of the control group were used as thresholds to determine agreement between them in further analysis. Sensitivity, specificity, and positive and negative predictive values of an ultrasound Tdi cutoff for detecting histologic atrophy were calculated. Agreement between two ultrasound observers was also assessed. RESULTS: Thirty-five ventilated organ donors and 5 ventilated controls were included, without differences in basic characteristics. CSA and Tdi were lower in donors than in controls. All donors presented lower CSA, but only 74% lower Tdi regarding control group thresholds. The cut-off value for lower diaphragm expiratory thickness (Tdi < 1.7 mm) presented a sensitivity of 73%, a specificity of 67%, a positive predictive value of 96% and a negative predictive value of 17% for determining the presence of diaphragm atrophy (CSA < 2851 µm2). CONCLUSIONS: Diaphragm atrophy and thickness reduction is associated to MV. While a lower Tdi in diaphragm ultrasound is a good tool for diagnosing atrophy, normal or increased Tdi cannot rule atrophy out showing that both parameters should not be considered as synonymous.

Gene expression profile of epithelial-mesenchymal transition in tumours of patients with nonsmall cell lung cancer: the influence of COPD.

Epithelial-mesenchymal transition (EMT) is involved in the pathophysiology of lung cancer (LC) and COPD, and the latter is an important risk factor for LC. We hypothesised that the EMT gene expression profile and signalling cascade may differ in LC patients with COPD from those with no respiratory diseases. In lung tumour specimens obtained through video-assisted thoracoscopic surgery from LC (n=20, control group) and LC-COPD patients (n=30), gene expression (quantitative real-time PCR amplification) of EMT markers SMAD3, SMAD4, ZEB2, TWIST1, SNAI1, ICAM1, VIM, CDH2, MMP1 and MMP9 was detected. In lung tumours of LC-COPD compared to LC patients, gene expression of SMAD3, SMAD4, ZEB2 and CDH2 significantly declined, while no significant differences were detected for the other analysed markers. A significant correlation was found between pack-years (smoking burden) and SMAD3 gene expression among LC-COPD patients. LC-COPD patients exhibited mild-to-moderate airway obstruction and a significant reduction in diffusion capacity compared to LC patients. In lung tumour samples of patients with COPD, several markers of EMT expression, namely SMAD3, SMAD4, ZEB2 and CDH2, were differentially expressed suggesting that these markers are likely to play a role in the regulation of EMT in patients with this respiratory disease. Cigarette smoke did not seem to influence the expression of EMT markers in this study. These results have potential clinical implications in the management of patients with LC, particularly in those with underlying respiratory diseases.

Surgical Risk Following Anatomic Lung Resection in Thoracic Surgery: A Prediction Model Derived from a Spanish Multicenter Database. / Riesgo quirúrgico tras resección pulmonar anatómica en cirugía torácica. Modelo predictivo a partir de una base de datos nacional multicéntrica.

INTRODUCTION: The aim of this study was to develop a surgical risk prediction model in patients undergoing anatomic lung resections from the registry of the Spanish Video-Assisted Thoracic Surgery Group (GEVATS). METHODS: Data were collected from 3,533 patients undergoing anatomic lung resection for any diagnosis between December 20, 2016 and March 20, 2018. We defined a combined outcome variable: death or Clavien Dindo grade IV complication at 90 days after surgery. Univariate and multivariate analyses were performed by logistic regression. Internal validation of the model was performed using resampling techniques. RESULTS: The incidence of the outcome variable was 4.29% (95% CI 3.6-4.9). The variables remaining in the final logistic model were: age, sex, previous lung cancer resection, dyspnea (mMRC), right pneumonectomy, and ppo DLCO. The performance parameters of the model adjusted by resampling were: C-statistic 0.712 (95% CI 0.648-0.750), Brier score 0.042 and bootstrap shrinkage 0.854. CONCLUSIONS: The risk prediction model obtained from the GEVATS database is a simple, valid, and reliable model that is a useful tool for establishing the risk of a patient undergoing anatomic lung resection.

Markers of Stroma in Lung Cancer: Influence of COPD / Marcadores estromales en el cáncer de pulmón: la influencia de la enfermedad pulmonar obstructiva crónica

BACKGROUND: Stroma, mainly composed by fibroblasts, extracellular matrix (ECM) and vessels, may play a role in tumorigenesis and cancer progression. Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for LC. We hypothesized that markers of fibroblasts, ECM and endothelial cells may differ in tumors of LC patients with/without COPD. METHODS: Markers of cultured cancer-associated fibroblasts and normal fibroblasts [CAFs and NFs, respectively, vimentin and alpha-smooth muscle actin (SMA) markers, immunofluorescence in cultured lung fibroblasts], ECM, and endothelial cells (type I collagen and CD31 markers, respectively, immunohistochemistry) were identified in lung tumor and non-tumor specimens (thoracotomy for lung tumor resection) from 15 LC-COPD patients and 15 LC-only patients. RESULTS: Numbers of CAFs significantly increased, while those of NFs significantly decreased in tumor samples compared to non-tumor specimens of both LC and LC-COPD patients. Endothelial cells (CD31) significantly decreased in tumor samples compared to non-tumor specimens only in LC patients. No significant differences were seen in levels of type I collagen in any samples or study groups. CONCLUSIONS: Vascular endothelial marker CD31 expression was reduced in tumors of non-COPD patients, while type I collagen levels did not differ between groups. A rise in CAFs levels was detected in lung tumors of patients irrespective of airway obstruction. Low levels of CD31 may have implications in the overall survival of LC patients, especially in those without underlying airway obstruction. Identification of CD31 role as a prognostic and therapeutic biomarker in lung tumors of patients with underlying respiratory diseases warrants attention

ANTECEDENTES: El estroma, compuesto principalmente por fibroblastos, matriz extracelular (MEC) y vasos, puede desempeñar un papel en la génesis tumoral y la progresión del cáncer. La enfermedad pulmonar obstructiva crónica (EPOC) es un factor de riesgo independiente para el carcinoma de pulmón (CP). Nuestra hipótesis fue que los marcadores de fibroblastos, MEC y células endoteliales pueden variar en los tumores de los pacientes con CP con o sin EPOC. MÉTODOS: Se identificaron los marcadores de fibroblastos asociados al cáncer y los fibroblastos normales cultivados (FAC y FN, respectivamente; marcadores: vimentina y α-actina del músculo liso [SMA por sus siglas en inglés]; inmunofluorescencia en fibroblastos de pulmón cultivados) y marcadores de la MEC y las células endoteliales (marcadores: colágeno tipo I y CD31, respectivamente; inmunohistoquímica) en muestras de pulmón tumoral y no tumoral (toracotomía para resección de tumores pulmonares) de 15 pacientes con EPOC-CP y 15 pacientes con solo CP. RESULTADOS: El número de FAC aumentó de forma significativa, mientras que el de FN disminuyó significativamente en las muestras tumorales en comparación con las muestras no tumorales de pacientes con CP y EPOC-CP. Las células endoteliales (CD31) disminuyeron también de forma significativa en las muestras tumorales en comparación con las muestras no tumorales solo en los pacientes con CP. No se observaron diferencias significativas en los niveles de colágeno tipo I en ninguna muestra o grupo de estudio. CONCLUSIONES: La expresión del marcador vascular endotelial CD31 se redujo en los tumores de los pacientes sin EPOC, mientras que los niveles de colágeno tipo I no difirieron entre los grupos. Se detectó un aumento en los niveles de FAC en los tumores de pulmón de los pacientes, con independencia de la presencia de obstrucción de las vías respiratorias. Los niveles bajos de CD31 pueden tener implicaciones en la supervivencia general de los pacientes con CP, en especial, en aquellos sin obstrucción subyacente de las vías respiratorias. Convendría estudiar e identificar el papel del CD31 como biomarcador terapéutico y de pronóstico en los tumores de pulmón de pacientes con enfermedades respiratorias subyacentes

Preoperative Body Weight and Albumin Predict Survival in Patients With Resectable Lung Neoplasms: Role of COPD / El peso corporal preoperatorio y la albúmina predicen la supervivencia en pacientes con neoplasias de pulmón resecables: el papel de la EPOC

INTRODUCTION: The impact of preoperative nutritional status on survival in lung cancer (LC) patients with underlying chronic obstructive pulmonary disease (COPD) is still unclear. We hypothesized that presurgical nutritional assessment may differentially predict mortality in patients with resectable LC with moderate COPD and relatively well-preserved nutritional status. METHODS: Nutritional assessment [body mass index (BMI), blood parameters including albumin and protein levels, and body weight loss], and other clinical parameters [cigarette smoking (CS) history, LC staging and histological subtypes, COPD severity, lung function, and adjuvant therapy] were evaluated in 125 patients from the LC Mar Prospective Cohort: 87 LC-COPD patients and 38 LC patients without COPD before thoracotomy. Ten-year overall survival (OS) was analyzed in all patients. RESULTS: Prior to thoracotomy, in LC-COPD patients compared to LC, BMI and albumin declined relatively, low levels of the parameters BMI, albumin, and total proteins were associated with poorer 10-year survival, especially in the LC-COPD. CS burden also correlated with impaired survival. COPD per se worsened the prognosis in LC patients. CONCLUSIONS: In the present cohort of LC patients with resectable tumors and relatively well-preserved nutritional status, the parameters BMI and blood albumin and protein levels measured prior to thoracotomy predicted OS, especially in those with COPD. These are clinically relevant findings, since values of those nutritional parameters were within the normal ranges in the majority of the analyzed patients. A thorough nutritional preoperative assessment should be included in the study of patients with resectable LC, particularly in those with chronic airway obstruction

INTRODUCCIÓN: El impacto del estado nutricional preoperatorio en la supervivencia en pacientes con cáncer de pulmón (CP) y enfermedad pulmonar obstructiva crónica (EPOC) subyacente aún no está claro. Planteamos la hipótesis de que la evaluación nutricional prequirúrgica puede predecir diferencialmente la mortalidad en pacientes con CP resecable y EPOC moderada, y un estado nutricional relativamente bien conservado. MÉTODOS: Se evaluaron el estado nutricional (índice de masa corporal [IMC], parámetros sanguíneos que incluyeron los niveles de albúmina y proteínas y pérdida de peso corporal) y otros parámetros clínicos (antecedentes de tabaquismo, estadificación del CP y el subtipo histológico, gravedad de la EPOC, función pulmonar y terapia adyuvante) en 125 pacientes de la cohorte prospectiva de CP del Hospital del Mar: 87 pacientes con EPOC-CP y 38 pacientes con CP sin EPOC antes de la toracotomía. Se analizó la supervivencia global (SG) a 10 años en todos los pacientes. RESULTADOS: Antes de la toracotomía, en los pacientes con EPOC-CP, el IMC y la albúmina disminuyeron en comparación con los del grupo de CP; los niveles bajos de los parámetros IMC, albúmina y proteínas totales se asociaron con menor supervivencia a 10 años, especialmente en los EPOC-CP. La carga tabáquica también se correlacionó con una disminución en la supervivencia. La EPOC empeoró per se el pronóstico en pacientes con CP. CONCLUSIONES: En la presente cohorte de pacientes con CP resecable y estado nutricional relativamente bien conservado, el IMC y los niveles de albúmina y proteínas en sangre medidos antes de la toracotomía predijeron la SG, especialmente en aquellos con EPOC. Estos son hallazgos clínicamente relevantes, ya que los valores de esos parámetros nutricionales estaban dentro de los rangos normales en la mayoría de los pacientes analizados. Se debe incluir una evaluación nutricional preoperatoria exhaustiva en el estudio de pacientes con CP resecable, particularmente en aquellos con obstrucción pulmonar crónica

Markers of Stroma in Lung Cancer: Influence of COPD.

BACKGROUND: Stroma, mainly composed by fibroblasts, extracellular matrix (ECM) and vessels, may play a role in tumorigenesis and cancer progression. Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for LC. We hypothesized that markers of fibroblasts, ECM and endothelial cells may differ in tumors of LC patients with/without COPD. METHODS: Markers of cultured cancer-associated fibroblasts and normal fibroblasts [CAFs and NFs, respectively, vimentin and alpha-smooth muscle actin (SMA) markers, immunofluorescence in cultured lung fibroblasts], ECM, and endothelial cells (type I collagen and CD31 markers, respectively, immunohistochemistry) were identified in lung tumor and non-tumor specimens (thoracotomy for lung tumor resection) from 15 LC-COPD patients and 15 LC-only patients. RESULTS: Numbers of CAFs significantly increased, while those of NFs significantly decreased in tumor samples compared to non-tumor specimens of both LC and LC-COPD patients. Endothelial cells (CD31) significantly decreased in tumor samples compared to non-tumor specimens only in LC patients. No significant differences were seen in levels of type I collagen in any samples or study groups. CONCLUSIONS: Vascular endothelial marker CD31 expression was reduced in tumors of non-COPD patients, while type I collagen levels did not differ between groups. A rise in CAFs levels was detected in lung tumors of patients irrespective of airway obstruction. Low levels of CD31 may have implications in the overall survival of LC patients, especially in those without underlying airway obstruction. Identification of CD31 role as a prognostic and therapeutic biomarker in lung tumors of patients with underlying respiratory diseases warrants attention.

Preoperative Body Weight and Albumin Predict Survival in Patients With Resectable Lung Neoplasms: Role of COPD.

INTRODUCTION: The impact of preoperative nutritional status on survival in lung cancer (LC) patients with underlying chronic obstructive pulmonary disease (COPD) is still unclear. We hypothesized that presurgical nutritional assessment may differentially predict mortality in patients with resectable LC with moderate COPD and relatively well-preserved nutritional status. METHODS: Nutritional assessment [body mass index (BMI), blood parameters including albumin and protein levels, and body weight loss], and other clinical parameters [cigarette smoking (CS) history, LC staging and histological subtypes, COPD severity, lung function, and adjuvant therapy] were evaluated in 125 patients from the LC Mar Prospective Cohort: 87 LC-COPD patients and 38 LC patients without COPD before thoracotomy. Ten-year overall survival (OS) was analyzed in all patients. RESULTS: Prior to thoracotomy, in LC-COPD patients compared to LC, BMI and albumin declined relatively, low levels of the parameters BMI, albumin, and total proteins were associated with poorer 10-year survival, especially in the LC-COPD. CS burden also correlated with impaired survival. COPD per se worsened the prognosis in LC patients. CONCLUSIONS: In the present cohort of LC patients with resectable tumors and relatively well-preserved nutritional status, the parameters BMI and blood albumin and protein levels measured prior to thoracotomy predicted OS, especially in those with COPD. These are clinically relevant findings, since values of those nutritional parameters were within the normal ranges in the majority of the analyzed patients. A thorough nutritional preoperative assessment should be included in the study of patients with resectable LC, particularly in those with chronic airway obstruction.

Increased PARP Activity and DNA Damage in NSCLC Patients: The Influence of COPD.

(1) Background: Lung cancer (LC) is a major leading cause of death worldwide. Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 are key players in cancer. We aimed to assess PARP-1 and PARP-2 expression and activity and DNA damage in tumors and non-tumor lungs from patients with/without chronic obstructive pulmonary disease (COPD). (2) Methods: Lung tumor and non-tumor specimens were obtained through video-assisted thoracoscopic surgery (VATS) in LC patients with/without underlying COPD (two groups of patients, n = 15/group). PARP-1 and PARP-2 expression (ELISA), PARP activity (PARP colorimetric assay kit) and DNA damage (immunohistochemistry) levels were identified in all samples. (3) Results: Both PARP-1 and PARP-2 expression levels were significantly lower in lung tumors (irrespective of COPD)compared to non-tumor specimens, while DNA damage and PARP activity levels significantly increased in lung tumors compared to non-tumor specimens only in LC-COPD patients. PARP-2 expression was positively correlated with smoking burden in LC-COPD patients. (4) Conclusions: In lung tumors of COPD patients, an overactivation of PARP enzyme was observed. A decline in PARP-1 and PARP-2 protein expression was seen in lung tumors irrespective of COPD. Other phenotypic features (airway obstruction) beyond cancer may account for the increase in PARP activity seen in the tumors of patients with underlying COPD.

Spanish Video-Assisted Thoracic Surgery Group: Method, Auditing, and Initial Results From a National Prospective Cohort of Patients Receiving Anatomical Lung Resections / Grupo Español de Cirugía Torácica Videoasistida: Método, Auditoría y Resultados Iniciales de una Cohorte Nacional Prospectiva de Pacientes Tratados con Resección Pulmonar Anatómica

INTRODUCTION: Our study sought to know the current implementation of video-assisted thoracoscopic surgery (VATS) for anatomical lung resections in Spain. We present our initial results and describe the auditing systems developed by the Spanish VATS Group (GEVATS). METHODS: We conducted a prospective multicentre cohort study that included patients receiving anatomical lung resections between 12/20/2016 and 03/20/2018. The main quality controls consisted of determining the recruitment rate of each centre and the accuracy of the perioperative data collected based on six key variables. The implications of a low recruitment rate were analysed for "90-day mortality" and "Grade IIIb-V complications". RESULTS: The series was composed of 3533 cases (1917 VATS; 54.3%) across 33 departments. The centres' median recruitment rate was 99% (25-75th:76-100%), with an overall recruitment rate of 83% and a data accuracy of 98%. We were unable to demonstrate a significant association between the recruitment rate and the risk of morbidity/mortality, but a trend was found in the unadjusted analysis for those centres with recruitment rates lower than 80% (centres with 95-100% rates as reference): grade IIIb-V OR = 0.61 (p = 0.081), 90-day mortality OR = 0.46 (p = 0.051). CONCLUSIONS: More than half of the anatomical lung resections in Spain are performed via VATS. According to our results, the centre's recruitment rate and its potential implications due to selection bias, should deserve further attention by the main voluntary multicentre studies of our speciality. The high representativeness as well as the reliability of the GEVATS data constitute a fundamental point of departure for this nationwide cohort

INTRODUCCIÓN: Nuestro estudio buscó conocer el grado de implementación actual de la cirugía toracoscópica asistida por video (VATS, por sus siglas en inglés) para las resecciones pulmonares anatómicas en España. Presentamos nuestros resultados iniciales y describimos los sistemas de auditoría desarrollados por el grupo español de VATS (GEVATS). MÉTODOS: Realizamos un estudio de cohortes prospectivo multicéntrico que incluyó pacientes que fueron tratados con resecciones pulmonares anatómicas entre el 20/12/2016 y el 20/03/2018. Los controles de calidad principales consistieron en determinar la tasa de reclutamiento de cada centro y la precisión de los datos perioperatorios recolectados en base a seis variables clave. Se analizaron las implicaciones de una baja tasa de reclutamiento para "mortalidad a los 90 días" y "complicaciones de grado IIIb-V". RESULTADOS: La serie estaba compuesta por 3533 casos (1917 VATS; 54,3%) en 33 servicios. La mediana de la tasa de reclutamiento de los centros fue del 99% (p25-p75: 76-100%), con una tasa de reclutamiento global del 83% y una precisión de los datos del 98%. No pudimos demostrar una asociación significativa entre la tasa de reclutamiento y el riesgo de morbi-mortalidad, pero se encontró una tendencia en el análisis no ajustado para aquellos centros con tasas de reclutamiento inferiores al 80% (usando los centros con tasas de 95-100% como referencia): OR = 0,61 para el grado IIIb-V (p = 0,081), OR = 0,46 para la mortalidad a los 90 días (p = 0,051). CONCLUSIONES: Más de la mitad de las resecciones pulmonares anatómicas en España se realizan a través de VATS. Según nuestros resultados, la tasa de reclutamiento del centro y sus posibles implicaciones debido al sesgo de selección, deberían recibir más atención por parte de los principales estudios multicéntricos voluntarios de nuestra especialidad. La alta representatividad y la confiabilidad de los datos de GEVATS constituyen un punto de partida fundamental para esta cohorte nacional

Rotura traqueal yatrogénica en el contexto de la actual infección por COVID-19. A propósito de 2 casos / Tracheal Trauma in the Context of the Current Infection by COVID-19. About 2 Cases

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Rotura traqueal yatrogénica en el contexto de la actual infección por COVID-19. A propósito de 2 casos / Tracheal trauma in the context of the current infection by COVID-19. About 2 cases

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B Cells and Tertiary Lymphoid Structures Influence Survival in Lung Cancer Patients with Resectable Tumors.

Immune profile of B and T cells and tertiary lymphoid structures (TLSs) may differ in tumors of lung cancer (LC) patients with/without chronic obstructive pulmonary disease (COPD), and may also influence patient survival. We sought to analyze: (1) TLSs, germinal centers (GCs), B and T cells, and (2) associations of the immune biomarkers with the patients' 10-year overall survival (OS). TLSs (numbers and area), B [cluster of differentiation (CD) 20], and T (CD3), and GCs cells were identified in both tumor and non-tumor specimens (thoracotomy) from 90 LC-COPD patients and 43 LC-only patients. Ten-year OS was analyzed in the patients. Immune profile in tumors of LC-COPD versus LC: TLS numbers and areas significantly decreased in tumors of LC-COPD compared to LC patients. No significant differences were observed in tumors between LC-COPD and LC patients for B or T cells. Immune profile in tumors versus non-tumor specimens: TLS areas and B cells significantly increased, T cells significantly decreased in tumors of both LC and LC-COPD patients. Survival: in LC-COPD patients: greater area of TLSs and proportion of B cells were associated with longer survival rates. The immune tumor microenvironment differs in patients with underlying COPD and these different phenotypes may eventually impact the response to immunotherapy in patients with LC.

Immune Cell Subtypes and Cytokines in Lung Tumor Microenvironment: Influence of COPD.

BACKGROUND: The immune microenvironment plays a role in tumorigenesis. Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for lung cancer (LC). We hypothesized that immune profile characterized by T regulatory (Treg), natural killer (NK), and plasma cells, as well as interleukin (IL)-10 and interferon-gamma, may differ within tumors of LC patients with/without COPD. METHODS: Treg (anti-CD3 and anti-forkhead boxP3 antibodies), NK (anti-NCR1 antibody), IgG (anti-CD138-IgG antibody), IgA (anti-CD138-IgA antibody) using immunohistochemistry, and both IL-10 and interferon-gamma (ELISA) were quantified in tumor and non-tumor specimens (thoracotomy for lung tumor resection) from 33 LC-COPD patients and 20 LC-only patients. RESULTS: Immune profile in tumor versus non-tumor specimens: Treg cell counts significantly increased in tumors of both LC and LC-COPD patients, while in tumors of the latter group, IgG-secreting plasma cells significantly decreased and IL-10 increased. No significant differences were seen in levels of NK cells, IgA-secreting cells, IgA/IgG, or interferon-gamma. Immune profile in tumors of LC-COPD versus LC: No significant differences were observed in tumors between LC-COPD and LC patients for any study marker. CONCLUSIONS: Immune cell subtypes and cytokines are differentially expressed in lung tumors, and the presence of COPD elicited a decline in IgG-secreting plasma cell levels but not in other cell types.

Spanish Video-Assisted Thoracic Surgery Group: Method, Auditing, and Initial Results From a National Prospective Cohort of Patients Receiving Anatomical Lung Resections.

INTRODUCTION: Our study sought to know the current implementation of video-assisted thoracoscopic surgery (VATS) for anatomical lung resections in Spain. We present our initial results and describe the auditing systems developed by the Spanish VATS Group (GEVATS). METHODS: We conducted a prospective multicentre cohort study that included patients receiving anatomical lung resections between 12/20/2016 and 03/20/2018. The main quality controls consisted of determining the recruitment rate of each centre and the accuracy of the perioperative data collected based on six key variables. The implications of a low recruitment rate were analysed for "90-day mortality" and "Grade IIIb-V complications". RESULTS: The series was composed of 3533 cases (1917 VATS; 54.3%) across 33 departments. The centres' median recruitment rate was 99% (25-75th:76-100%), with an overall recruitment rate of 83% and a data accuracy of 98%. We were unable to demonstrate a significant association between the recruitment rate and the risk of morbidity/mortality, but a trend was found in the unadjusted analysis for those centres with recruitment rates lower than 80% (centres with 95-100% rates as reference): grade IIIb-V OR=0.61 (p=0.081), 90-day mortality OR=0.46 (p=0.051). CONCLUSIONS: More than half of the anatomical lung resections in Spain are performed via VATS. According to our results, the centre's recruitment rate and its potential implications due to selection bias, should deserve further attention by the main voluntary multicentre studies of our speciality. The high representativeness as well as the reliability of the GEVATS data constitute a fundamental point of departure for this nationwide cohort.

Endoplasmic reticulum stress and unfolded protein response in diaphragm muscle dysfunction of patients with stable chronic obstructive pulmonary disease.

Respiratory muscle dysfunction is common in patients with chronic obstructive pulmonary disease (COPD). Chronic contractile activity induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in animals (animals and humans). We hypothesized that the respiratory muscle dysfunction associated with COPD may upregulate ER stress and UPR expression in diaphragm of stable patients with different degrees of airway obstruction and normal body composition. In diaphragm muscle specimens of patients with mild and moderate-to-severe COPD with preserved body composition and non-COPD controls (thoracotomy because of lung localized neoplasms), expression of protein misfolding (ER stress) and UPR markers, proteolysis and apoptosis (qRT-PCR and immunoblotting), and protein aggregates (lipofuscin, histology) were quantified. All patients and non-COPD controls were also clinically evaluated: lung and muscle functions and exercise capacity. Compared with non-COPD controls, patients exhibited mild and moderate-to-severe airflow limitation and diffusion capacity and impaired exercise tolerance and diaphragm strength. Moreover, compared with the controls, in the diaphragm of the COPD patients, slow-twitch fiber proportions increased, gene expression but not protein levels of protein disulfide isomerase family A member 3 and phosphatidylinositol 3-kinase catalytic subunit type 3 were upregulated, and no significant differences were found in markers of UPR transmembrane receptor pathways (activating transcription factor-6, inositol-requiring enzyme-1α, and protein kinase-like ER kinase), lipofuscin aggregates, proteolysis, or apoptosis. In stable COPD patients with a wide range of disease severity, reduced diaphragm force of contraction, and normal body composition, ER stress and UPR signaling were not induced in the main respiratory muscle. These findings imply that ER stress and UPR are probably not involved in the documented diaphragm muscle dysfunction (reduced strength) observed in all the study patients, even in those with severe airflow limitation. Hence, in stable COPD patients with normal body composition, therapeutic strategies targeted to treat diaphragm muscle dysfunction should not include UPR modulators, even in those with a more advanced disease. NEW & NOTEWORTHY In stable chronic obstructive pulmonary disease patients with a wide range of disease severity, diaphragm muscle weakness, and normal body composition, endoplasmic reticulum stress and unfolded protein response (UPR) signaling were not induced in the main respiratory muscle. These findings imply that endoplasmic reticulum stress and UPR are not involved in the documented diaphragm muscle dysfunction observed in the study patients, even in those with severe airflow limitation. In stable chronic obstructive pulmonary disease patients with normal body composition, therapeutic strategies should not include UPR modulators.

Combined aerobic exercise and high-intensity respiratory muscle training in patients surgically treated for non-small cell lung cancer: a pilot randomized clinical trial.

BACKGROUND: Lung resection surgery further decreases exercise capacity and negatively affects respiratory muscle function in patients with non-small cell lung cancer (NSCLC). The best design for exercise interventions in these patients has not been determined yet. AIM: To assess the impact of aerobic exercise and high-intensity respiratory muscle training on patient outcomes following lung cancer resection surgery. DESIGN: Prospective, single-blind, pilot randomized controlled trial. SETTING: Outpatient cardiopulmonary rehabilitation unit of two university hospitals. POPULATION: Thirty-seven patients with NSCLC after tumor resection. METHODS: Patients were randomly assigned to exercise training or usual post-operative care. The training program consisted of aerobic exercises and high-intensity respiratory muscle training (24 supervised sessions, 3 per week, 8 weeks). Primary outcome was exercise capacity assessed with peak oxygen uptake (VO2peak) during cardiopulmonary exercise test. Secondary outcomes included changes in respiratory muscle strength, levels of serum insulin growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3), and quality of life assessed with the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) questionnaire. RESULTS: The 8-week training program was associated with significant improvement in VO2peak (2.13 mL/Kg/min [95%CI 0.06 to 4.20]), maximal inspiratory and expiratory pressures (18.96 cmH2O [95% CI 2.7 to 24.1] and 18.58 cmH2O [95% CI 4.0 to 33.1], respectively) and IGFBP-3 (0.61 µg/mL [%95 CI 0.1 to 1.12]). No significant differences were observed in the EORTC QLQ-C30. CONCLUSIONS: An 8-week exercise program consisting of aerobic exercise and high-intensity respiratory muscle training improved exercise capacity, respiratory muscle strength, and serum IGFBP-3 levels in NSCLC patients after lung resection. There was no impact on the other outcomes assessed. CLINICAL REHABILITATION IMPACT: A combination of aerobic exercise and respiratory muscle training could be included in the rehabilitation program of deconditioned patients with NSCLC after lung resection surgery.

Profile of epigenetic mechanisms in lung tumors of patients with underlying chronic respiratory conditions.

Background: Chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and epigenetic events underlie lung cancer (LC) development. The study objective was that lung tumor expression levels of specific microRNAs and their downstream biomarkers may be differentially regulated in patients with and without COPD. Methods: In lung specimens (tumor and non-tumor), microRNAs known to be involved in lung tumorigenesis (miR-21, miR-200b, miR-126, miR-451, miR-210, miR-let7c, miR-30a-30p, miR-155 and miR-let7a, qRT-PCR), DNA methylation, and downstream biomarkers were determined (qRT-PCR and immunoblotting) in 40 patients with LC (prospective study, subdivided into LC-COPD and LC, N = 20/group). Results: Expression of miR-21, miR-200b, miR-210, and miR-let7c and DNA methylation were greater in lung tumor specimens of LC-COPD than of LC patients. Expression of downstream markers PTEN, MARCKs, TPM-1, PDCD4, SPRY-2, ETS-1, ZEB-2, FGFRL-1, EFNA-3, and k-RAS together with P53 were selectively downregulated in tumor samples of LC-COPD patients. In these patients, tumor expression of miR-126 and miR-451 and that of the biomarkers PTEN, MARCKs, FGFRL-1, SNAIL-1, P63, and k-RAS were reduced. Conclusions: Biomarkers of mechanisms involved in tumor growth, angiogenesis, migration, and apoptosis were differentially expressed in tumors of patients with underlying respiratory disease. These findings shed light into the underlying biology of the reported greater risk to develop LC seen in patients with chronic respiratory conditions. The presence of an underlying respiratory disease should be identified in all patients with LC as the differential biological profile may help determine tumor progression and the therapeutic response. Additionally, epigenetic events offer a niche for pharmacological therapeutic targets.

Systemic and Tumor Th1 and Th2 Inflammatory Profile and Macrophages in Lung Cancer: Influence of Underlying Chronic Respiratory Disease.

INTRODUCTION: Chronic respiratory conditions, especially chronic obstructive pulmonary disease (COPD), and inflammatory events underlie lung cancer (LC). We hypothesized that profiles of T helper 1 and T helper 2 cytokines and type 1 and type 2 macrophages (M1 and M2) are differentially expressed in lung tumors and blood of patients with NSCLC with and without COPD and that the ratio M1/M2 specifically may influence their survival. METHODS: In blood, inflammatory cytokines (determined by enzyme-linked immunosorbent assay) were quantified in 80 patients with LC (60 with LC and COPD [the LC-COPD group] and 20 with LC only [the LC-only group]) and lung specimens (tumor and nontumor) from those undergoing thoracotomy (20 in the LC-COPD group and 20 in the LC-only group). RESULTS: In the LC-COPD group compared with in the LC-only group, systemic levels of tumor necrosis factor-α, interleukin-2 (IL-2), transforming growth factor-ß, and IL-10 were increased, whereas vascular endothelial growth factor and IL-4 levels were decreased. In lung tumors, levels of tumor necrosis factor-α, transforming growth factor-ß, and IL-10 were higher than in nontumor parenchyma in the LC-COPD group, whereas IL-2 and vascular endothelial growth factor levels were higher in tumors of both the LC-only and LC-COPD groups. Compared with in nontumor lung, M1 macrophage counts were reduced whereas M2 counts were increased in tumors of both patient groups, and the M1/M2 ratio was higher in the LC-COPD group than the LC-only group. M1 and M2 counts did not influence patients' survival. CONCLUSIONS: The relative predominance of T helper 1 cytokines and M1 macrophages in the blood and tumors of patients with underlying COPD imply that a stronger proinflammatory pattern exists in these patients. Inflammation should not be targeted systematically in all patients with LC. Screening for the presence of underlying respiratory diseases and identification of the specific inflammatory pattern should be carried out in patients with LC, at least in early stages of their disease.