Video-assisted mediastinoscopic lymphadenectomy (VAMLA): Mature results for staging non-small cell lung cancer with normal mediastinum.

OBJECTIVES: The aim of this study is to analyze the accuracy of video-assisted mediastinoscopic lymphadenectomy (VAMLA) and the unsuspected (u) N2/3 rates in patients with non-small cell lung cancer (NSCLC) and normal mediastinum by integrated positron emission tomography-computed tomography. METHODS: Prospective observational single-center study of 603 consecutive VAMLAs from 2010 to 2022. EXCLUSION CRITERIA: other indications (n = 32), tumors different from NSCLC (n = 91), and clinical (c) N2/3 tumors by positron emission tomography-computed tomography (n = 46). Systematic nodal dissection was the gold standard to validate negative VAMLAs. Those patients with negative VAMLA and missing reference standard test were excluded. uN2/3 rates were analyzed in the global series and in the subgroups of tumors according to their clinical nodal and tumor categories. Pathologic findings were reviewed, and staging values were calculated. RESULTS: Three hundred eighty-three patients with cN0/1 NSCLC underwent VAMLA. Staging values of VAMLA were: sensitivity, 0.98 (95% CI, 0.92-0.99); negative predictive value, 0.99 (95% CI, 0.98-1); and diagnostic accuracy, 0.99 (95% CI, 0.98-1). The uN2/3 rate for the whole series (N = 383) was 18.8%. The uN2/3 rates according to presurgical nodal and tumor categories determined by positron emission tomography computed tomography were: 3.6% (4 out of 111) in cT1N0; 16.3% (18 out of 110) in cT2N0; 10.25% (4 out of 39) in cT3N0; and 32% (7 out of 22) in cT4N0. Forty-two percent (39 out of 93) in cN1; complication rate was 7%. CONCLUSIONS: This series of NSCLC with normal mediastinum staged by VAMLA demonstrates a high accuracy of this technique and a high rate of uN2/3 disease (specially in cN1 and cT4N0). VAMLA could be considered the reference staging procedure for staging cN0/1 NSCLC.

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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Transcervical videomediastino-thoracoscopy.

Although technical advances in non-invasive and minimally invasive approaches to lung and pleural cancer diagnosis and staging have become more widely available and accurate, surgical techniques remain the gold standard in assessing the extent of loco-regional involvement. Precise surgical staging of lung or pleural tumours is pivotal in the selection of surgical candidates and for predicting survival. In some patients, both mediastinal and pleural exploration may be needed for many different reasons. Transcervical videomediastino-thoracoscopy (VMT) combines simultaneously the exploration of both the mediastinum and the pleural cavities through a single cervical incision, allowing for biopsies or sampling of the mediastinal lymph nodes, lymphadenectomy and pleuropulmonary assessment (mainly pleural effusions, tumour involvement of the visceral and parietal pleura and pulmonary nodules). Thoracic surgeons should be aware of this combined surgical approach and completely familiar with classical indications and technical details of the transcervical approach to the mediastinum and thoracoscopic exploration of the pleural cavities.

Video-Assisted Mediastinoscopic Lymphadenectomy for Staging Non-Small Cell Lung Cancer.

BACKGROUND: The aim of this study was to evaluate the results of video-assisted mediastinoscopic lymphadenectomy (VAMLA) for staging of non-small cell lung cancer (NSCLC). METHODS: This was a prospective observational study of all consecutive VAMLAs performed from January 2010 to April 2015 for staging NSCLC. For left lung cancers, extended cervical videomediastinoscopy was added to explore the subaortic and paraaortic nodes. Patients with negative VAMLA results underwent tumor resection and lymphadenectomy of the remaining nodes. Those with N2-3 disease underwent chemoradiation. The rate of unsuspected pathologic (p)N2-3 was analyzed in the global series and in the subgroups of patients according to their nodal status diagnosed by imaging and metabolic techniques. RESULTS: One hundred sixty VAMLAs were performed for staging NSCLC (138 tumors were clinical (c)N0-1 based on imaging techniques). The rate of unsuspected N2-3 disease was 18% for the whole series: 40.7% for cN1, 22.2% for cN0 and tumor size greater than or equal to 3 cm, and 6.4% for cN0 and tumor size less than 3 cm. Staging values were sensitivity, 0.96 (95% confidence interval [CI], 0.81-99.3); specificity, 1 (95% CI, 0.97-1); positive predictive value, 1 (95% CI, 0.87-1); negative predictive value, 0.99 (95% CI, 0.95-0.99); and diagnostic accuracy, 0.99 (95% CI, 0.96-0.99). The complication rate was 5.9%. CONCLUSIONS: VAMLA is a feasible and highly accurate technique. The high rate of unsuspected mediastinal node disease diagnosed by VAMLA in patients with cN1 or cN0 disease and tumor size larger than 3 cm suggests that preresection lymphadenectomies should be included in the current staging algorithms.

Tumor, node and metastasis classification of lung cancer--M1a versus M1b--analysis of M descriptors and other prognostic factors.

INTRODUCTION: The current edition of the tumor, node and metastasis (TNM) classification of lung cancer (LC) divides the presence of metastasis (M1) into two categories: M1a and M1b, depending on its anatomical location. To assess this new classification, the survival and the M descriptors of LC patients with metastatic disease registered by the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery II (GCCB-S-II), were analyzed. METHODS: Non-small cell lung cancer (NSCLC) patients, with M1a or M1b disease, included in the GCCB-S-II, from April 2009 to December 2010, staged in accordance with the prospective staging project protocol of the International Association for the Study of Lung Cancer (IASLC), and with complete TNM staging and follow-up data, were studied. The overall survival associated with each M1 category and each M descriptor, besides other prognostic factors (sex, age, performance status [PS] and others) were analyzed by univariate and multivariate models. RESULTS: 640 NSCLC patients (195 M1a and 445 M1b) were included. M1b tumors had significantly worse survival than M1a tumors (p < 0.001). The prognostic value of M1 category was independent from other prognostic variables such as PS, weight loss, and others. The number of metastatic sites (isolated versus multiple) and the number of lesions (single versus multiple) in patients with isolated metastasis showed prognostic value, especially in those with brain metastasis. CONCLUSION: The current division of the M1 category into two subsets (M1a and M1b) is warranted by their prognostic significance. The number of metastatic sites and the number of lesions in patients with isolated metastasis should be taken into account, because they also have prognostic relevance.

Survival of patients with unsuspected pN2 non-small cell lung cancer after an accurate preoperative mediastinal staging.

BACKGROUND: The aim of this study is to analyze the survival of patients with non-small cell lung cancer (NSCLC) without clinical suspicion of mediastinal lymph node involvement who underwent complete resection and whose tumors were finally proven to be pathologic N2 (pN2). METHODS: This is a retrospective study of a prospective database from January 2004 to December 2010. A total of 621 patients with NSCLC were staged and operated according to the European Society of Thoracic Surgeons guidelines. After exclusions (previous induction treatment, carcinoid tumors, small cell carcinomas), 540 patients were analyzed; 406 (75%) required surgical exploration of the mediastinum and 134 (25%) underwent surgery directly. Survival analysis was performed by the Kaplan-Meier method and the log-rank test was used for comparisons. RESULTS: Thirty (5.5%) patients had unsuspected pN2 and complete resection was achieved in 27 (90%). Three- and 5-year survival rates were 87% and 81%, respectively, for patients with a true negative result of the protocol (pN0-1), and 79% and 40%, respectively, for those with a false negative result (unsuspected pN2) (p < 0.0001). CONCLUSIONS: The rate of unsuspected pN2 in patients whose tumors were staged according to the European Society of Thoracic Surgeons guidelines was low. The survival of this group of patients was better than expected. Therefore, resection of properly staged unsuspected pN2 NSCLC is reasonable and should not be avoided if complete resection can be achieved.

Registro del Grupo Cooperativo de Cáncer de Pulmón-II de la Sociedad Española de Neumología y Cirugía Torácica. Estudio descriptivo / The Spanish Society of Pulmonology and Thoracic Surgery Lung Cancer Cooperative Group-II Registry. A Descriptive Study

Introducción y objetivos: La 7.a edición de la clasificación TNM, junto a ventajas indudables, presenta limitaciones. El Comité de Estadificación de la International Association for the Study of Lung Cancer (IASLC) ha diseñado un estudio prospectivo internacional para perfeccionar esa clasificación. En el área de Oncología de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) se constituyó un grupo de cirujanos torácicos y neumólogos que creó un registro de nuevos casos de cáncer de pulmón (CP) para participar en ese proyecto. El objetivo del presente trabajo es describir las características principales de los pacientes incluidos. Material y métodos: Estudio prospectivo, observacional, multicéntrico y multirregional de recogida de datos (epidemiológicos, clínicos, funcionales, terapéuticos y, especialmente, de extensión anatómica), según protocolo de la IASLC, para analizar su valor pronóstico. Resultados: Se incluyen 2.419 (83,6% hombres) pacientes de 28 hospitales. El 96% de los hombres y el 54% de las mujeres eran fumadores o exfumadores. Se practicó TC de tórax/abdomen en más del 90% y PET/TC en el 51,5% de los casos. Entre 1.035 pacientes sometidos a cirugía, el 77% tenían estadios tempranos ( I a hasta II b), y de los tratados con otros medios, el 61,6% tenían estadio IV . La comorbilidad respiratoria fue mayor en hombres (47,9% frente al 21,4%). La estirpe más común fue adenocarcinoma (34%), especialmente en mujeres no fumadoras (69,5%). Conclusiones: La proporción de mujeres y adenocarcinomas aumenta entre los casos de CP en España, así como los resecados en estadio temprano (AU)

Introduction and objectives: The seventh edition of the TNM classification, together with undeniable advantages, has limitations. The International Association for the Study of Lung Cancer (IASLC) Staging Committee has designed an international prospective study to improve this classification. A group of thoracic surgeons and pulmonologists was established in the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) Oncology area, and created a registry of new lung cancer (LC) cases to participate in this project. The aim of this paper is to describe the main characteristics of the patients included. Materials and methods: Prospective, observational, multicentre, multiregional data collection (epidemiological, clinical, therapeutic and, especially, anatomical extension) study, according to the IASLC protocol, to analyse its prognostic value. Results: Two thousand, four hundred and nineteen patients (83.6% men) from 28 hospitals were included. Ninety-six percent of the men and 54% of the women were smokers or ex-smokers. Chest/abdominal computed tomography (CT) scanning was performed in over 90% and positron emission tomography (PET)/CT scanning in 51.5% of cases. Among the 1035 patients who underwent surgery, 77% had early stages ( I a to II b), and 61.6% of those treated using other methods had stage IV . Respiratory comorbidity was higher in men (47.9% versus 21.4%). The most common histological subtype was adenocarcinoma (34%), especially in non-smoking women (69.5%). Conclusions: The proportion of women and adenocarcinomas, as well as those resected at an early stage, increased among LC cases in Spain (AU)

The Spanish Society of Pulmonology and Thoracic Surgery Lung Cancer Cooperative Group-II registry. A descriptive study.

INTRODUCTION AND OBJECTIVES: The seventh edition of the TNM classification, together with undeniable advantages, has limitations. The International Association for the Study of Lung Cancer (IASLC) Staging Committee has designed an international prospective study to improve this classification. A group of thoracic surgeons and pulmonologists was established in the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) Oncology area, and created a registry of new lung cancer (LC) cases to participate in this project. The aim of this paper is to describe the main characteristics of the patients included. MATERIALS AND METHODS: Prospective, observational, multicentre, multiregional data collection (epidemiological, clinical, therapeutic and, especially, anatomical extension) study, according to the IASLC protocol, to analyse its prognostic value. RESULTS: Two thousand, four hundred and nineteen patients (83.6% men) from 28 hospitals were included. Ninety-six percent of the men and 54% of the women were smokers or ex-smokers. Chest/abdominal computed tomography (CT) scanning was performed in over 90% and positron emission tomography (PET)/CT scanning in 51.5% of cases. Among the 1035 patients who underwent surgery, 77% had early stages (ia to iib), and 61.6% of those treated using other methods had stage iv. Respiratory comorbidity was higher in men (47.9% versus 21.4%). The most common histological subtype was adenocarcinoma (34%), especially in non-smoking women (69.5%). CONCLUSIONS: The proportion of women and adenocarcinomas, as well as those resected at an early stage, increased among LC cases in Spain.

Extended cervical mediastinoscopy: mature results of a clinical protocol for staging bronchogenic carcinoma of the left lung.

OBJECTIVE: The objective of this study is to evaluate the accuracy of extended cervical mediastinoscopy (ECM) in the staging of bronchogenic carcinoma (BC) of the left lung based on our updated experience. METHODS: From 1998 to 2003, 89 patients underwent routine ECM for staging of BC of the left lung. In 2004, routine positron emission tomography (PET) was included in our staging protocol and ECM was reserved for those with positive mediastinal or hilar PET images, large lymph nodes on computed tomography (CT) scan or central tumours. Following this protocol, from 2004 to 2010, we performed 132 selective ECM. ECM was considered positive when metastatic nodes or tumour involvement directly in the subaortic or para-aortic regions was confirmed pathologically. Patients with negative ECM underwent subsequent thoracotomy for tumour resection and systematic nodal dissection (SND). RESULTS: Two hundred and twenty-one ECMs were performed from 1998 to 2010 (89 routine and 132 selective). In the routine ECM protocol, four cases were positive and thoracotomy was contraindicated. The remaining 85 patients were operated and five had nodal disease in subaortic (LN5) or para-aortic (LN6) stations. In the selective ECM protocol (n = 188), 132 patients underwent ECM and in 19 it was positive; the remaining 113 patients underwent thoracotomy and SND found involved LN5 or LN6 in six patients; the other 56 patients underwent direct thoracotomy and four had positive LN5 or LN6. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of ECM were 0.67, 1, 1, 0.94 and 0.95, respectively. The staging values of routine/selective ECM protocols were 0.44/0.65, 1/1, 1/1, 0.94/0.94 and 0.94/0.95, respectively. CONCLUSIONS: Selective ECM protocol according to CT and PET findings has high negative predictive value and accuracy. Therefore, its selective use is recommended because it saves around 30% ECM without decreasing staging values of the current protocol.

Repeat mediastinoscopy in all its indications: experience with 96 patients and 101 procedures.

OBJECTIVE: To evaluate the accuracy of repeat mediastinoscopy (reMS) in all its indications, and 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 (NSCLC). METHODS: From July 1992 to February 2009, 96 patients (87 men; median age: 61.3 years), underwent 101 reMSs (five patients required a second reMS) for the following indications: restaging after induction therapy for pathologically proven N2 disease (84 cases), inadequate first mediastinoscopy (five), metachronous second primary (six) and recurrent lung cancer (six). Patients with N2-NSCLC, who had received induction therapy and had positive reMS, underwent definitive chemotherapy or chemoradiotherapy. Patients in whom reMS was negative underwent thoracotomy for lung resection and systematic nodal dissection (SND). SND was considered the gold standard to compare the negative results of reMS. Pathologic findings were reviewed and staging values were calculated using the standard formulas. Follow-up data were completed in January 2010, and survival analysis was performed by the Kaplan-Meier method. RESULTS: In the group of reMS for restaging after induction therapy, the staging values were: sensitivity 0.74, specificity 1, positive predictive value 1, negative predictive value 0.79 and diagnostic accuracy 0.87. We also determined the diagnostic value of this technique according to the type of induction treatment. In terms of accuracy, no statistically significant differences were found. Median survival time in patients with true negative reMS was 51.5 months (95% confidence interval (CI) 0-112), and in the combined group of patients with positive and false-negative reMS, median survival time was 11 months (95% CI 7.6-14.1) (p=0.0001). In the group of miscellaneous indications, all staging values were 1. CONCLUSION: ReMS is feasible in all the indications described. After induction therapy, it is a useful procedure to select patients for lung resection with high accuracy, independently of the induction treatment used or the intensity of the first mediastinoscopy. The persistence of lymph node involvement after induction therapy has a poor prognosis. Therefore, techniques providing cytohistological evidence of nodal downstaging are advisable to avoid unnecessary thoracotomies.

Surgical sealant for preventing air leaks after pulmonary resections in patients with lung cancer.

BACKGROUND: Postoperative air leak is a frequent complication after pulmonary resection for lung cancer. It may cause serious complications, such as empyema, or prolong the need for chest tube and hospitalization. Different types of surgical sealants have been developed to prevent or to reduce postoperative air leaks. A systematic review was therefore undertaken to evaluate the evidence on their effectiveness. OBJECTIVES: To evaluate the effectiveness of surgical sealants in preventing or reducing postoperative air leaks after pulmonary resection for lung cancer. SEARCH STRATEGY: We searched the electronic databases MEDLINE (1966 to September 2008), EMBASE (1974 to September 2008), and the Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library, Issue 3, 2008) and listed references. We hand searched conference proceedings to identify published and unpublished trials. SELECTION CRITERIA: We included randomized controlled clinical trials in which standard closure techniques plus a sealant were compared with the same intervention with no use of any sealant in patients undergoing elective pulmonary resection provided that a large proportion of the patients studied had undergone pulmonary resection for lung cancer. DATA COLLECTION AND ANALYSIS: Four reviewers independently selected the trials to be included in the review, assessed methodological quality of each trial and extracted data using a standardized form. Because of several limitations, narrative synthesis was used at this stage. MAIN RESULTS: Sixteen trials, with 1642 randomized patients in total were included. In thirteen trials there were differences between treatment and control patients in reducing postoperative air leaks. This reduction proved to be significant in six trials. Three trials showed a significant reduction in time to chest drain removal in the treatment group. In two trials, the percentage of patients with persistent air leak was significantly smaller in the treatment group. Finally, three trials including 352 patients showed a statistically significant reduction in length of hospital stay. AUTHORS' CONCLUSIONS: Surgical sealants reduce postoperative air leaks and time to chest drain removal but this reduction is not always associated with a reduction in length of postoperative hospital stay. Therefore, systematic use of surgical sealants with the objective of reducing hospital stay cannot be recommended at the moment. More and larger randomized controlled clinical trials are needed.

Extended cervical mediastinoscopy in the staging of bronchogenic carcinoma of the left lung.

OBJECTIVE: To evaluate the technical feasibility and the sensitivity, specificity and accuracy of extended cervical mediastinoscopy (ECM) in the staging of bronchogenic carcinoma (BC) of the left lung. METHODS: From 1998 to 2003, 89 patients underwent routine ECM for staging of BC of the left lung. In 2004, positron emission tomography (PET) was included in our staging protocol and ECM was reserved for those with positive mediastinal or hilar PET images, large lymph nodes on computed tomography (CT) scan or central tumours. From 2004 to 2007 we performed selective ECM in 67 patients. ECM was considered positive when metastatic nodes or tumour involvement directly in the subaortic or para-aortic regions was confirmed pathologically. One hundred and forty-three patients with negative ECM underwent subsequent thoracotomy for tumour resection and systematic nodal dissection. Pathological findings were reviewed and staging values were calculated. RESULTS: One hundred and fifty-six patients underwent ECM (89 routine and 67 selective). In 13, ECM was positive and thoracotomy was contraindicated. The rest of the patients were operated. We performed 88 lobectomies, 34 pneumonectomies, 6 wedge resections, 13 exploratory thoracotomies and 2 parasternal mediastinotomies. Lymphadenectomy specimens showed tumour involvement of subaortic lymph nodes in 8 patients. Complication rate was 2%: two cases of mediastinitis, one ventricular fibrillation, and one superficial surgical wound infection. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of routine/selective ECM were: 0.45/0.75, 1/1, 1/1, 0.94/0.95, 0.94/0.95, respectively. CONCLUSION: ECM is a feasible staging technique that allows ruling out subaortic and para-aortic nodal disease with high negative predictive value, accuracy and sensitivity. Its indication based on the CT and PET findings seems more advisable that its routine use to stage bronchogenic carcinoma of the left lung.

Accuracy and survival of repeat mediastinoscopy after induction therapy for non-small cell lung cancer in a combined series of 104 patients.

OBJECTIVE: Precise restaging of non-small cell lung cancer after induction therapy is of utmost importance. Remediastinoscopy remains a controversial procedure. In a combined, updated series of two thoracic centres, accuracy and survival of remediastinoscopy were determined. METHODS: From November 1994 to August 2005, remediastinoscopy was performed in 104 patients (98 men, 6 women) after induction therapy for locally advanced non-small cell lung cancer. Mean age was 64.3 years (range 38-85). Neoadjuvant chemotherapy was given in 79 patients and chemoradiotherapy in 25. Follow-up data were completed in January 2007. RESULTS: Remediastinoscopy was technically feasible in all patients except for one who died due to perioperative haemorrhage. Remediastinoscopy was positive in 40 patients and negative in 64; the latter group underwent thoracotomy. There were 17 false-negative remediastinoscopies. Sensitivity of remediastinoscopy was 71%, specificity 100% and accuracy 84%. Follow-up was complete for all patients. Sixty-nine died, mostly of distant metastases. Median survival time for the whole group was 18 months (95% confidence interval 11-25). Median survival time in patients with a positive remediastinoscopy was 14 months (95% confidence interval 8-20), with a negative remediastinoscopy 28 months (95% confidence interval 15-41) and with a false-negative remediastinoscopy 24 months (95% confidence interval 3-45). In univariate analysis the difference between positive and negative remediastinoscopies was highly significant (p=0.001). In a multivariate analysis including sex, age, histology, centre, and nodal status at remediastinoscopy, only nodal status was a significant independent prognostic factor (p=0.008). CONCLUSIONS: Remediastinoscopy is a valuable restaging procedure after induction therapy. Persisting mediastinal nodal involvement proven at remediastinoscopy heralds a poor prognosis.

Estadificación mediastínica del cáncer de pulmón en el siglo XXI: un reto de carácter multidisciplinario / Mediastinic staging of lung cancer in the XXI century: a multidisciplinary challenge

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Identificación del carcinoma broncogénico N0cy / Identifying cyN0 bronchogenic carcinoma

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