Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung Adenocarcinoma

Funding: supported by a La Caixa Foundation grant and the Spanish Association Against Cancer (PROYE18012ROSE)EGFR mutation-positive lung adenocarcinoma (LUAD) displays impaired phosphorylation of ERK and Src-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. We hypothesize that SHP2 expression could be predictive in patients positive with resected EGFR mutation versus patients with EGFR wild-type LUAD. We examined resected LUAD cases from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1, and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction. The activity of SHP2 inhibitors plus erlotinib were tested in EGFR -mutant cell lines and analyzed by cell viability assay, Western blot, and immunofluorescence. A total of 50 of 100 EGFR mutation-positive LUADs relapsed, among them, patients with higher SHP2 mRNA expression revealed shorter progression-free survival, in comparison with those having low SHP2 mRNA (hazard ratio: 1.83; 95% confidence interval: 1.05-3.23; p = 0.0329). However, SHP2 was not associated with prognosis in the remaining 167 patients with wild-type EGFR. In EGFR -mutant cell lines, the combination of SHP099 or RMC-4550 (SHP2 inhibitors) with erlotinib revealed synergism via abrogation of phosphorylated AKT (S473) and ERK1/2 (T202/Y204). Although erlotinib translocates phosphorylated SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocates SHP2 into the cytoplasm membrane, limiting AKT and ERK1/2 activation. Elevated SHP2 mRNA levels are associated with recurrence in resected EGFR mutation-positive LUADs, but not in EGFR wild-type. EGFR tyrosine kinase inhibitors can enhance SHP2 activation, hindering adjuvant therapy. SHP2 inhibitors could improve the benefit of adjuvant therapy in EGFR mutation-positive LUADs

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

Grupo español de cirugía torácica asistida por videoimagen: método, auditoría y resultados iniciales de una cohorte nacional prospectiva de pacientes tratados con resecciones anatómicas del pulmón

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

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Estadificación y reestadificación ganglionar mediastínica de máxima certeza en el tratamiento del carcinoma broncogénico

[spa] La clasificación de extensión anatómica del cáncer de pulmón, definida según el tumor primario, los ganglios linfáticos y las metástasis (TNM), permite agrupar tumores con una extensión anatómica similar y diferenciarlos en estadios con diferentes tasas de supervivencias. En los pacientes con carcinoma broncogénico sin extensión extratorácica, la afectación ganglionar mediastínica es el factor más importante a la hora de determinar el pronóstico y definir la actitud terapéutica. Las guías para la estadificación ganglionar mediastínica preoperatoria de la European Society of Thoracic Surgeons (ESTS) y de la American College of Chest Physicians (ACCP) recomiendan una exploración del mediastino con certificación cito-histológica, por métodos mínimamente invasivos o quirúrgicos cuando la tomografía computerizada (TC) detecta ganglios mediastínicos de tamaño patológico, cuando los tumores son de localización central o cuando la tomografía por emisión de positrones (PET) muestra una hipercaptación mediastínica o hiliar. El objetivo fundamental de la presente tesis, que se basa en dos artículos publicados y relacionados entre sí, es evaluar la rentabilidad diagnóstica de las técnicas quirúrgicas que proporcionan la mayor certeza diagnóstica en la estadificación y la reestadificación del mediastino. El primer trabajo es un estudio retrospectivo observacional en el que se analizaron los resultados de 101 remediastinoscopias (reMC) realizadas entre julio de 1992 y febrero de 2009. El análisis de resultados se centró principalmente en la indicación más frecuente de esta técnica, la reestadificación de carcinoma broncogénico con afectación ganglionar mediastínica en pacientes tratados con quimioterapia o quimioradioterapia de inducción (84 pacientes). La sensibilidad, especificidad, valor predictivo positivo, valor predictivo negativo y exactitud diagnóstica de la técnica fueron 0,74, 1, 1, 0,79 y 0,87, respectivamente. También se analizó la rentabilidad de la reMC según la intensidad de la primera MC y el tipo de tratamiento de inducción utilizado sin encontrarse diferencias significativas en ninguna de las dos situaciones. En referencia a la supervivencia, los resultados obtenidos a partir de los resultados de la reMC fueron los siguientes: 51,5 meses para los pacientes con una reMC verdadera negativa, y 11 meses para el conjunto de pacientes con una reMC positiva o falsamente negativa. En referencia a la tasa de morbi-mortalidad relacionada con la reMC, se describe una tasa de complicaciones del 4%, y una muerte por hemorragia secundaria a la lesión del tronco arterial braquiocefálico. El segundo trabajo, es un estudio prospectivo y observacional de 185 pacientes sometidos a linfadenectomía por videomediastinoscopia (VAMLA), entre enero de 2010 y abril de 2015. Después de aplicar los criterios de exclusión, sólo se analizaron aquellos pacientes con diagnóstico final de carcinoma de célula no pequeña (n=160). La sensibilidad, especificidad, valor predictivo positivo, valor predictivo negativo y exactitud diagnóstica de la técnica fueron 0,96, 1, 1, 0,99 y 0,99, respectivamente. La tasa global de N2 detectados con el VAMLA fue del 18%. La tasa de N2 según la clasificación clínica TNM (por TC y PET) fue: a) 40,7% para los tumores N1c; b) 22,2% para los tumores N0c de tamaño mayor a los 3 cm. y c) 6,4% para los tumores N0c de tamaño igual o inferior a los 3 cm. En referencia a la tasa de morbilidad relacionada con la VAMLA, se describe una tasa global del 5.9%. No hubo ninguna muerte relacionada con el procedimiento. Con todos los datos obtenidos, se concluye que ambas técnicas, la reMC y la VAMLA deberían integrarse en los algoritmos de estadificación y reestadificación.[eng] Preoperative mediastinal nodal assessment is essential to define prognosis and guide treatment for patients with lung cancer. The current North American and European guidelines for preoperative mediastinal nodal staging for non-small cell lung cancer (NSCLC) recommend tissue confirmation with endoscopic techniques or with surgical staging when computed tomography shows enlarged mediastinal nodes, when positron emission tomography shows an increased uptake in the mediastinum or the hilum, and in central tumours. This thesis is based on two published and related articles, the objectives of which are: to evaluate the accuracy of repeat mediastinoscopy (reMS), to analyse survival in the group of patients who underwent induction chemotherapy or chemoradiotherapy for pathologically proven stage III-N2 non-small-cell lung cancer and to evaluate the results of video-assisted mediastinoscopic lymphadenectomy (VAMLA) for staging NSCLC. The first publication is a retrospective study (1992-2009) that includes 101 repeat mediastinoscopies (reMSs). The staging values of this technique in its main indication (restaging after induction therapy) were: sensitivity 0.74, specificity 1, positive predictive value 1, negative predictive value 0.79 and diagnostic accuracy 0.87. The median survival time in patients with true negative reMS was 51.5 months, and in the combined group of patients with positive and false-negative reMS, the median survival time was 11 months. The difference between these two groups was significant (p= 0.0001). The complication rate was 4%. One patient died due to haemorrhage from the origin of the innominate artery. The second publication is a prospective study (2010-2015) of all consecutive VAMLA for staging NSCLC (n=160). The rate of unsuspected N2–3 disease was 18% for the whole series: 40.7% for clinical (c) N1, 22.2% for cN0 and tumour size greater than 3 cm, and 6.4% for cN0 and tumour size less or equal than 3 cm. Staging values were sensitivity 0.96, specificity 1, positive predictive value 1, negative predictive value 0.99 and diagnostic accuracy 0.99. The complication rate was 5.9%. There were no deaths related to the procedure. Based on the results from these studies, it can be concluded that both techniques, reMS and VAMLA, should be included in the current staging and restaging algorithms

Cervical mediastinoscopy and video-assisted mediastinoscopic lymphadenectomy for the staging of non-small cell lung cancer

The staging of mediastinal lymph nodes is essential for planning the most adequate treatment for patients with non-small cell lung cancer (NSCLC). For this reason, the current American and European guidelines recommend obtaining tissue confirmation of any mediastinal abnormality seen on chest computed tomography (CT) and positron emission tomography (PET). This can be done by endoscopic techniques, such as endobronchial ultrasonographic fine-needle aspiration (EBUS-FNA), esophageal ultrasonographic FNA (EUS-FNA), or a combination of the two (CUS). Traditionally, surgical methods have been reserved to validate the negative results of minimally invasive endoscopic techniques. However, based on the latest evidence, cervical mediastinoscopy and video-assisted mediastinoscopic lymphadenectomy (VAMLA) have demonstrated their superiority over minimally invasive methods in terms of performance for those tumors with normal mediastinum [clinical (c) N0-1 by CT and PET]. Therefore, cervical mediastinoscopy and VAMLA should be considered in the staging algorithms of this particular subset of NSCLC, and in the other well-established indications