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Background Lung cancer is the most threatening malignant tumor to human health and life. Using a variety of machine learning algorithms and statistical analyses, this paper explores, discovers and demonstrates new indicators for the early diagnosis of lung cancer and their diagnostic performance from large samples of clinical data in the real world. Methods By applying machine learning methods, including minimum description length (MDL), naive Bayesian (NB), K-means (KM), nonnegative matrix factorization (NMF), and decision tree (DT), based on large sample data of 2,502 patients, we built a classification model and systematically explored differences in fibrinogen levels in different clinical stages of lung cancer between the sexes. We also validated the reliability of the model by testing it on a validation cohort of 447 patients. This report adheres to the "Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis" (TRIPOD) statement for the reporting of prediction models. Results The analysis revealed significant differences in fibrinogen levels, pleural effusion, chlorine levels, A-G ratio, glutamic-oxaloacetic transaminase and alkaline phosphatase levels as well as in sex composition between the early-stage lung cancer group and the middle-late-stage lung cancer group. The classification model created by the combination of fibrinogen, alkaline phosphatase and sex demonstrated good performance with an AUC of 73.5%. In addition, in males, a fibrinogen level of 2.94 g/L could initially serve as the upper limit for determining the early-stage lung cancer group, but a level of 3.91 g/L could be preliminarily used as a reference threshold for the lower limit for middle- to late-stage lung cancer. This latter level could also serve as the upper limit of the critical value for early-stage lung cancer in females. Conclusions An integrated application based on supervised and unsupervised machine learning algorithms could effectively explore the potential links contained in the clinical data and reveal the differences in fibrinogen levels in different clinical stages of lung cancer between the sexes, which could provide a new reference basis for lung cancer staging.

In lung cancer accurate assessment of the mediastinal lymph node status is of paramount importance for the stage assignment as well as crucial for the therapeutic plan. TAC and positron emission tomography (PET) are valuable tools to achieve a preliminary picture of the mediastinal staging but Endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) is considered the first choice for investigating mediastinal lymph nodes as recommended by updated guide-lines. Despite the EBUS-TBNA sensitivity is satisfactory, it is not high enough to exclude mediastinal lymph node metastases; therefore devices and technologies were implemented to increase its sensitivity. The purpose of this narrative review is to describe the tools aimed at correctly interpreting sonographic patterns during EBUS and maximizing the diagnostic accuracy of TBNA. The bibliographic research identified 354 articles potentially related to the purpose of the current review and after accurate reading we selected 21 articles. Eight articles focused on the sonographic features of lymph nodes found during EBUS, 2 papers considered the Doppler patterns and, finally, 18 studies analyzed the advantages of ultrasound elastography. Sonographic features, vascular patterns and ultrasound elastography have proved to be helpful in directing the operator to biopsy the most suspect lymph node, especially in patients with CT-negative and/or PET-negative mediastinum.

I thank the journal for the interest in our article (1) and Dr. Jantz for his thoughtful comments. I agree with Dr. Jantz’s stance on the importance of mediastinal staging for non-small cell lung cancer (NSCLC) and agree that data from investigations for lung cancer staging are established.

Complete and accurate staging for patients diagnosed with lung cancer to assess the extent of disease is of critical importance so that appropriate treatment recommendations may be provided (1). An incorrect clinical staging classification can lead to wrong decisions on withholding potentially curative resection as well as inappropriate nonsurgical definitive therapy and palliative treatment options. In their study, Navani and colleagues analyzed the accuracy of clinical staging for stage I–IIIa non-small cell lung cancer (NSCLC) (2).

Background Regarding the staging of mediastinal lymph nodes before lung cancer surgery, Endobronchial Ultrasound Transbronchial Needle Aspirations (EBUS-TBNA) have proven to be highly sensitive and specific as well as safe. Endoscopic Ultrasound Fine Needle Aspirations (EUS-FNA) plays an important role in the diagnosis and staging of thoracic diseases, including lung cancer. In this study we analysed all patients underwent endoscopic procedures in our endoscopic mediastinal ultrasound unit. Methods Between January 2013 and February 2018, we performed a total of 929 endoscopic procedures, 432 EBUS-TBNA and 497 EUS-FNA. Biopsy was performed at the following mediastinal sites: station 7 in 642 cases, at stations 8 and 9 in 211 cases; at station 3P and 4L in 27 and 114 cases respectively; with EUS we were able to perform biopsy at station 5 in 52 cases. Results A total of 841 patients showed a diagnosis of cancer: non-small cell lung cancer (NSCLC) in 645 patients, SCLC in 190 patients, neuroendocrine tumour in 5 patients and one patient with mesothelioma. 88 patients were negative for cancer. In terms of sensitivity, specificity and accuracy, the association between EUS-FNAb and EBUS-TBNAb showed a better quality on diagnosis compared to single procedures. EUS-FNA and EBUS-TBNA are safe, feasible, and highly sensitive techniques. Conclusions An endoscopic mediastinal ultrasound unit allows to perform a higher number of endoscopic procedures and improved the sensitivity and the accuracy of the minimally invasive hilar-mediastinal staging.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) plays a key role in the staging of lung cancer, which is crucial for allocation to surgical treatment. EBUS-TBNA is a complicated procedure and simulation-based training is helpful in the first part of the long learning curve prior to performing the procedure on actual patients. New trainees should follow a structured training programme consisting of training on simulators to proficiency as assessed with a validated test followed by supervised practice on patients. The simulation-based training is superior to the traditional apprenticeship model and is recommended in the newest guidelines. EBUS-TBNA and oesophageal ultrasound-guided fine needle aspiration (EUS-FNA or EUS-B-FNA) are complementary to each other and the combined techniques are superior to either technique alone. It is logical to learn and to perform the two techniques in combination, however, for lung cancer staging solely EBUS-TBNA simulators exist, but hopefully in the future simulation-based training in EUS will be possible.

Background: In evaluating patients with suspected lung cancer, it is important to not only obtain a tissue diagnosis, but also to obtain enough tissue for both histologic and molecular analysis in order to appropriately stage the patient with a safe and efficient strategy. The diagnostic approach may often be dependent on local resources and practice patterns rather than current guidelines. We Describe lung cancer staging at two large academic medical centers to identify the impact different procedural approaches have on patient outcomes. Methods: We conducted a retrospective cohort study of all patients undergoing a lung cancer diagnostic evaluation at two multidisciplinary centers during a 1-year period. Identifying complication rates and the need for multiple biopsies as our primary outcomes, we developed a multivariate regression model to determine features associated with complications and need for multiple biopsies. Results: Of 830 patients, 285 patients were diagnosed with lung cancers during the study period. Those staged at the institution without an endobronchial ultrasound (EBUS) program were more likely to require multiple biopsies (OR 3.62, 95% CI: 1.71–7.67, P=0.001) and suffer complications associated with the diagnostic procedure (OR 10.2, 95% CI: 3.08–33.58, P Conclusions: Lung cancer evaluation at centers with a dedicated EBUS program results in fewer biopsies and complications than at multidisciplinary counterparts without an EBUS program.

Multi-institutional studies of endobronchial-ultrasound transbronchial needle aspiration (EBUS-TBNA) for mediastinal staging in lung cancer are scarce. It is unclear if the high diagnostic performance of EBUS-TBNA reported by experts' guidelines can be generally achieved.This is a retrospective study performed in five tertiary referral centers of thoracic surgery in Italy, to assess the EBUS-TBNA diagnostic performance in patients with non-small cell lung cancer (NSCLC). Patient inclusion criteria were: both genders;18 years old; with suspect/confirmed NSCLC; undergoing EBUS-TBNA for mediastinal node enlargement at computed tomography (size1 cm, ≤3 cm) and/or pathological uptake at positron emission tomography. Altogether we included 485 patients [male, 366; female, 119; median age, 68 years (IQR, 61-74 years)] undergoing mediastinal staging between January 2011 and July 2016. All EBUS-TBNAs were performed by experienced bronchoscopists, without pre-defined quality standards. Depending on usual practice in each center, EBUS-TBNA was done under conscious sedation, with 21- or 22-Gauge (G) needle, and specimen preparation was cell-block, or cytology slides, or core-tissue. Sampling was classified inadequate in absence of lymphocytes, or when sample was insufficient. We analyzed the EBUS-TBNA procedural steps likely to influence the rate of adequate samplings (diagnostic yield).EBUS-TBNA sensitivity, negative predictive value (NPV) and accuracy respectively were 90%, 78% and 93% in the whole cohort. At multivariate analysis, use of 21-G needle was associated with better diagnostic yield (P0.001). Center and specimen processing technique were not independent factors affecting EBUS-TBNA diagnostic yield.In this multicentric study, EBUS-TBNA was a highly sensitive and accurate method for NSCLC mediastinal node staging. Results indicate better performance of EBUS-TBNA with 21-G needle, and suggest that specimen processing technique could be chosen according to the local practice preference.

The 8th edition of the tumor, node and metastasis (TNM) classification of lung cancer will be enacted in January 2017. The aim of this study was to analyze the survival differences among the three new categories of metastatic disease: intrathoracic metastasis (M1a), single extrathoracic metastasis (M1b) and multiple extrathoracic metastases (M1c) in our cohort of patients with non-small cell lung cancer (NSCLC).This is a retrospective single-center study including NSCLC patients with metastatic disease at diagnosis. Patients were divided into three groups (M1a, M1b, M1c). Overall survival (OS) within and between these subgroups was calculated using the Kaplan-Meier method.A total of 288 patients were included (112 M1a, 28 M1b and 148 M1c). Median OS of M1c was significantly worse than M1a or M1b tumors (P0.001). No significant differences were found among the M1a descriptors (pleural/pericardial nodules/effusion, bilateral tumor nodules or both descriptors) (P=0.722) and between M1a and M1b tumors (P=0.517). OS of patients with one metastasis in a single organ was not significantly different from OS of patients with two metastases in a single organ (P=0.180). Among M1c tumors, OS was significantly better in patients with multiple metastases in a single organ than in patients with multiple metastases in multiple organs (P=0.001).Our results support the proposal to keep the M1a category unchanged in the 8th edition as well as the proposed restructuring of the M1b in the new M1b and M1c categories. However, our results raise questions about the definition of oligometastatic disease and, consequently, the criteria of M1b and M1c category.

Lung cancer staging remains a moving target. Since the first TNM staging system was established by Mountain and colleagues there have been seven revisions (1,2). A jaded viewer may understandably feel that these revisions have proven to be refinements more than paradigm shifts.

We compared the performance of 7th and 8th edition of the Union for International Cancer Control (UICC) / American Joint Committee on Cancer (AJCC) TNM staging for non-small cell lung cancer (NSCLC) in non-metastatic (stage I-III) North American cohort undergoing primary radiation treatment.Newly diagnosed NSCLC between (Jan 2011 - Dec 2014) were screened through a Canadian Provincial Cancer Registry. Clinico-radiologically and pathologically confirmed non-metastatic NSCLC undergoing primary radiation treatment were included. Kaplan-Meier methods, Cox proportional hazard regression and Akaike information criterion (AIC) were applied to evaluate discriminatory ability and prognostic performance of 7th and 8th edition of staging systems.In this cohort of 295 patients, 8th edition stages IA3, IB, IIA, IIB, IIIA, IIIB, and IIIC showed progressive increase in the hazard ratio compared to best stage IA2 (8th edition IA3 vs IA2: HR 1.72; IB vs IA2: HR 2.04; IIA vs IA2: HR 2.66; IIB vs IA2: HR 2.91; IIIA vs IA2: HR 3.38; IIIB vs IA2: HR 3.62 and IIIC vs IA2: HR 8.22). In a multivariate model, 8th edition stage grouping had smaller AIC of 2342.08 compared to 7th edition 2349.55, confirming better performance. International Association for the Study of Lung Cancer (IASLC) map based nodal categorization N1, N2 and N3, showed good survival and hazard discrimination over stage N0 (1.39, 1.48 and 2.16 respectively).In an independent cohort of non-metastatic NSCLC undergoing primary radiation treatment, improved performance of 8

Lung cancer is one of the most common solid malignant disease and an accurate staging is required for planning the most appropriate treatment. Surgery or local radiotherapy are the elective treatment for localized disease, however, the presence of mediastinal malignant lymph nodes can affect the role of surgery as a first-line therapy and a chemotherapy and/or radiotherapy treatment are recommended. Currently endoscopic ultrasound (EUS) in the mediastinum has brought the important advantage of a minimal-invasive diagnostic approach for the diagnosis and staging of malignant conditions, having the possibility of sampling lesions or lymph nodes in real-time. EUS' diagnostic capabilities have increased over time and currently it represents an excellent approach for the staging of lung cancer, especially combined to endobronchial ultrasound (EBUS). Last generation EUS equipments (echoendoscopes, ultrasound processors, needles) and tools [contrast-enhanced EUS (CH-EUS), elastography] can help the endosonographer during the ultrasound evaluation and they can increase the accuracy of lung cancer staging. A systematic method of evaluation of all the visible lymph nodes stations is fundamental to complete the lung cancer staging, as well as a correct endoscopic room organization of the equipments, healthcare personnel and devices.

Lung cancer is the leading cause of cancer related deaths worldwide. Accurate staging of the mediastinum is essential to determine the appropriate treatment plan in patients with potentially operable non-small cell lung cancers (NSCLC). Traditionally, the gold standard test in mediastinal staging has been cervical mediastinoscopy. However, this procedure is invasive, requires general anesthesia, and is associated with significant risk. Training in endoscopic ultrasound (EUS) techniques in addition to endobronchial ultrasound (EBUS) allows for diagnosis and complete staging of lung cancer in a single session, thereby decreasing healthcare cost, time delays, increased sedation time, and patient discomfort. With its superior cost-effectiveness and reduced risk profile compared to conventional mediastinoscopy, endoscopic approach has replaced mediastinoscopy as the initial step in lung cancer staging and diagnosis. Here we discuss the utility of EUS along with combined EBUS with EUS, and highlight some of the technical aspects of the procedure. We will review the current role of EUS technique for the evaluation of mediastinal adenopathy and staging of lung cancer. We will also briefly discuss its use in diagnosing mediastinal infection and granulomatous lesions in the thoracic cavity.

Background: Carcinoids now constitute complex tumours which require a multidisciplinary approach and long-term follow-up. Surgical intervention is nowadays confirmed as the mainstay of treatment.Methods: From 1980 to 2015, EMETNE-SEPAR collected 1,339 patients treated surgically for bronchial carcinoid (1,154 typical and 185 atypical carcinoids). Standard and conservative procedures were considered with regard to surgical approach. All the patients with carcinoid were pathologically coded following the standards of the 7th edition 2009 TNM lung cancer staging. Statistical analyses were performed in order to determine whether histology, nodal affectation and surgical technique were associated with significant differences in survival, presence of metastases and local recurrence.Results: The influence of the surgical procedure on overall survival, the presence of metastases and local recurrence were demonstrated as no significant in our sample in central tumours (P>0.05). Sublobar resections in peripheral tumours are related to a decrease in survival in typical carcinoids (P=0.008) with nodal involvement and an increased number of recurrences in atypical carcinoids without nodal involvement (P=0.018).Conclusions: In central typical carcinoid, the use of lung-sparing bronchoplastic techniques could influence local recurrence in some cases. This observation demands the intraoperative pathologic verification of an adequate surgical margin by frozen section. Peripheral typical carcinoids have been surgically treated, occasionally, by sublobar resection. However, in peripheral atypical carcinoid after a limited sublobar resection the observed increase of the probability of local recurrence makes it, in our opinion, not advisable.

As co-coordinator of the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery and Chair of the Staging and Prognostic Factors Committee of the IASLC, Prof. Ramon Rami-Porta has been dedicated to lung cancer staging research for almost 35 years. Well-known of his contribution in fighting with lung cancer, Prof. Rami-Porta is very dynamic both in the clinical practice and academic arena.

Background: Lung cancer is the leading cause of cancer death in several countries. Surgical resection is a potentially curative treatment for non-small cell lung cancer (NSCLC), but tumor-specific factors and patient physical factors are important for postoperative prognosis. We conducted a retrospective study to investigate the link between sarcopenia and postoperative outcomes of surgical resected lung cancer patients, using preoperative CT for lung cancer staging. We also took in consideration the impact of sarcopenia on the national health cost and five years overall survival rate. Methods: Patients affected by NSCLC, stage I–IIIa, undergoing radical surgery with a mediastinal lymphadenectomy, were enrolled. Forty-two patients were considered suitable for the study, according to the inclusion and exclusion criteria. Among them, 28 were male and 14 female with average age of 72 years. The identification of Sarcopenia status was reached with the use of computed tomography (CT), with two slices at the level of the third lumbar level (L3), allowing the measure of the cross-sectional area from L3 to the iliac crest, expressed in cm 2 . We identified sarcopenic and non-sarcopenic patients, using the Sarcopenia Index. Results: Of the 42 patients suitable for the study, 13 were sarcopenic (31%) and 29 were non-sarcopenic (69%). Days of hospitalizations are 10 days in sarcopenic patients and 8.5 days in non-sarcopenic patients. Duration of permanence of the thoracic drainage is 7 days in sarcopenic patients and 5 days in non-sarcopenic patients. This is related with increased healthcare costs for sarcopenic patients (statistically significant: P Conclusions: Our study demonstrates the impact of sarcopenia in different ambits, from the clinical outcomes to the health expenditure. Preventing the insurgence of sarcopenia is essential to improve the postoperative outcomes, and for the Health System, to reduce healthcare-related costs.

More than half a century ago, Dr. Pierre Denoix devised the tumor, node, and metastasis (TNM) staging system of classifying cancer patients into distinct categories based on the anatomical extent of the tumor. Ever since, it has been adopted as the basis for estimating prognosis and selecting treatment in solid tumors. The Union for International Cancer Control (UICC) and the American Joint Committee for Cancer (AJCC) initially developed independent TNM classifications which were unified in 1987 for a single, consistent stage classification system.

Pathologic nodal stage is a key prognostic factor for patients with surgically resected lung cancer. We previously described the extent of missed intrapulmonary nodal metastasis in a cohort of patients treated at institutions in metropolitan Memphis, TN. With long-term follow-up, we now quantify the survival impact of missed nodal metastasis.We conducted a prospective cohort study to evaluate inadvertently discarded lymph nodes in re-dissected remnant lung resection specimens from lung cancer patients. Retrieved material was histologically examined and classified as lymph nodes with and without metastasis. Survival information was obtained from hospital cancer registries. We plotted survival distributions with the use of the Kaplan-Meier method and evaluated them with proportional hazards models that controlled for important demographic and clinical factors.The study included 110 patients who were 54% women and 69% white. Discarded lymph nodes with metastasis were found in 25 patients (23%). Patients with missed lymph node metastasis had an increased risk of death with an unadjusted hazard ratio of 2.0 (p = 0.06) and an adjusted hazard ratio of 1.4 (p = 0.45) compared with patients without missed lymph node metastasis. Patients with more than 2 missed lymph nodes with metastasis had 4.8 times the hazard of death (p = 0.0005) compared with patients without missed lymph node metastasis (adjusted hazard ratio 6.5, p = 0.0001).Metastasis to inadvertently discarded intrapulmonary lymph nodes from lung cancer resection specimens was associated with reduced survival. A more rigorous gross dissection protocol for lung cancer resection specimens may provide prognostically useful information.

An accurate staging of a malignant disease is imperative in order to plan pre- and post-operative therapy, define prognosis and compare studies. According to the European Society of Thoracic Surgeons (ESTS) guidelines a systematic lymph node (LN) dissection is recommended in all cases of pulmonary resection for non-small cell lung cancer (NSCLC). The current lung cancer staging system considers the lymphatic stations involved but not the number of LNs. Up to date, published scientific studies on hilar and mediastinal lymphadenectomy mainly have been regarded the type of LN dissection procedure after pulmonary resection (selected LN biopsy, LN sampling, systematic nodal dissection, lobe specific nodal dissection and extended LN dissection) focusing particularly on the comparison between mediastinal LN dissection (MLND) and mediastinal LN sampling (MLNS). Recently, further investigations have been concentrated on surgical approach (videothoracoscopic vs. thoracotomic approach) used to perform pulmonary resection and following LN dissection in order to achieve a complete mediastinal lymphadenectomy. This short synthesis aims to present the current experiences in this setting.

There is growing enthusiasm with lung resections by video-assisted thoracic surgery (VATS) technique in Brazil. The benefits of these minimally invasive procedures and their incorporation in the routine of many Brazilian centers produced a significant increase of sublobar and lobar resections in the country. The changes in our daily practice, including improvements in lung cancer staging, the rising of lung cancer screening programs and the analysis of several recent studies showing equivalent long-term outcomes with sublobar resections, while we treat often an elderly and poor performance population, have made the thoracic surgeon to look to a sublobar resection as a potentially curative procedure. We sought to analyze the Brazilian and institutional experience with VATS sublobar anatomical resections for treatment of benign and malignant diseases, and discuss technical aspects as well. Even though is much underreported, the outcomes of VATS segmentectomies resemble what is observed around the world and constitute in an effective surgery when well indicated. The Brazilian Society of Thoracic Surgery database is improving the notification by many centers and this better quality of data will provide us a deep knowledge about the results of our procedures national-wide.

Video-assisted thoracoscopic surgery (VATS) is a minimally invasive technique enabling a much more comfortable postoperative recovery. It can be a very useful approach in staging lung cancer addressing all components of TNM classification and, so, indicate the best therapeutic option in each case. In this article we describe the contribution of VATS in each of the components (T, N, M) and present some examples of our center.

While staging of lung cancer remains the leading indication for the use of mediastinoscopy, its utility is equally applicable to diagnosis of mediastinal lesions unrelated to bronchogenic carcinoma (1,2). The authors present a multitude of disease processes presenting with mediastinal adenopathy where obtaining tissue diagnosis is paramount. For these patients, as presented by the authors, expeditious diagnosis prevents further unnecessary evaluation and allows appropriate treatment initiation, few of which are surgical.

In the setting of a stage IV non-small cell lung cancer (NSCLC), oligometastatic patients represent a heterogeneous group whose incidence is increasing as far as with the adoption of new therapeutic regimens, the improvement of the molecular characterization assays and the increasing number of long-survivor patients. The oligometastatic state undergone a major revision with the introduction of the new TNM lung cancer staging system, being characterized by a different prognosis compared to multi-metastatic patients. Furthermore, the presence of a limited number of metastases imposes a local control especially when clonal selections occur during adjuvant therapy. In this regard, the review seeks to clarify the indications for surgical treatment by organ according to recent guidelines, by analyzing prognostic factors and outcome of patients. Although accurate patient stratification is mandatory, aggressive local control strategies represent a valid therapeutic approach in patients with oligometastatic NSCLC. At the same time, persevering with ablative strategies raises both medical and ethical issues about limits and reiteration, which certainly requires a deep reflection, being, on the other hand, in front of a metastatic disease.

Assessment of multifocal lung tumors and the distinction of synchronous primary tumors from intrapulmonary metastases represent an important problem as this decision significantly influences tumor staging and subsequent treatment strategies. Up to 8% of lung cancer patients present with two or more anatomically separate nodules. Yet, significant variability currently exists in treatments for these patients (1-4). Reasons for such ambiguity are that these patients represent a heterogeneous group of cohorts with marked difference in biological behaviors, survival, and recurrence pattern. Currently, no formal consensuses exist among clinicians in terms of staging, treatments, and follow-up.