Small Airway Disease in Pre-Chronic Obstructive Pulmonary Disease with Emphysema: A Cross-Sectional Study.

Rationale: Small airway disease is an important pathophysiological feature of chronic obstructive pulmonary disease (COPD). Recently, "pre-COPD" has been put forward as a potential precursor stage of COPD that is defined by abnormal spirometry findings or significant emphysema on computed tomography (CT) in the absence of airflow obstruction. Objective: To determine the degree and nature of (small) airway disease in pre-COPD using microCT in a cohort of explant lobes/lungs. Methods: We collected whole lungs/lung lobes from patients with emphysematous pre-COPD (n = 10); Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I (n = 6), II (n = 6), and III/IV (n = 7) COPD; and controls (n = 10), which were analyzed using CT and microCT. The degree of emphysema and the number and morphology of small airways were compared between groups, and further correlations were investigated with physiologic measures. Airway and parenchymal pathology was also validated with histopathology. Measurements and Main Results: The numbers of transitional bronchioles and terminal bronchioles per milliliter of lung were significantly lower in pre-COPD and GOLD stages I, II, and III/IV COPD compared with controls. In addition, the number of alveolar attachments of the transitional bronchioles and terminal bronchioles was also lower in pre-COPD and all COPD groups compared with controls. We did not find any differences between the pre-COPD and COPD groups in CT or microCT measures. The percentage of emphysema on CT showed the strongest correlation with the number of small airways in the COPD groups. Histopathology showed an increase in the mean chord length and a decrease in alveolar surface density in pre-COPD and all GOLD COPD stages compared with controls. Conclusions: Lungs of patients with emphysematous pre-COPD already show fewer small airways and airway remodeling even in the absence of physiologic airway obstruction.

A randomised phase II study of extended pleurectomy/decortication preceded or followed by chemotherapy in patients with early-stage pleural mesothelioma: EORTC 1205.

BACKGROUND: The role of surgery in pleural mesothelioma remains controversial. It may be appropriate in highly selected patients as part of a multimodality treatment including chemotherapy. Recent years have seen a shift from extrapleural pleuropneumonectomy toward extended pleurectomy/decortication. The most optimal sequence of surgery and chemotherapy remains unknown. METHODS: EORTC-1205-LCG was a multicentric, noncomparative phase 2 trial, 1:1 randomising between immediate (arm A) and deferred surgery (arm B), followed or preceded by chemotherapy. Eligible patients (Eastern Cooperative Oncology Group 0-1) had treatment-naïve, borderline resectable T1-3 N0-1 M0 mesothelioma of any histology. Primary outcome was rate of success at 20 weeks, a composite end-point including 1) successfully completing both treatments within 20 weeks; 2) being alive with no signs of progressive disease; and 3) no residual grade 3-4 toxicity. Secondary end-points were toxicity, overall survival, progression-free survival and process indicators of surgical quality. FINDINGS: 69 patients were included in this trial. 56 (81%) patients completed three cycles of chemotherapy and 58 (84%) patients underwent surgery. Of the 64 patients in the primary analysis, 21 out of 30 patients in arm A (70.0%; 80% CI 56.8-81.0%) and 17 out of 34 patients (50.0%; 80% CI 37.8-62.2%) in arm B reached the statistical end-point for rate of success. Median progression-free survival and overall survival were 10.8 (95% CI 8.5-17.2) months and 27.1 (95% CI 22.6-64.3) months in arm A, and 8.0 (95% CI 7.2-21.9) months and 33.8 (95% CI 23.8-44.6) months in arm B. Macroscopic complete resection was obtained in 82.8% of patients. 30- and 90-day mortality were both 1.7%. No new safety signals were found, but treatment-related morbidity was high. INTERPRETATION: EORTC 1205 did not succeed in selecting a preferred sequence of pre- or post-operative chemotherapy. Either procedure is feasible with a low mortality, albeit consistent morbidity. A shared informed decision between surgeon and patient remains essential.

An Overview of the Use of Anti-Angiogenic Agents in the Treatment of Thymic Epithelial Tumors.

Angiogenesis significantly influences the carcinogenesis of thymic epithelial tumors (TET). Both thymomas and thymic carcinoma (TC) overexpress VEGF-A and VEGFR-1 and -2. This review aims to provide an appraisal of the use of anti-angiogenics in the treatment of TET. The literature research identified 16 studies that were deemed eligible for further analysis. Seven studies assessed the clinical efficacy of sunitinib and five studies the use of apatinib and/or anlotinib. The multicenter Japanese phase II REMORA trial investigated the efficacy of lenvatinib, which is a multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The objective response rate was 38% (25.6-52%), which is the highest documented in TET that progressed after first-line chemotherapy. Anti-angiogenic agents may be useful in the treatment of TET, which are not amenable to curative treatment. Their toxicity profile seems to be acceptable. However, angiogenesis inhibitors do not appear to have a major influence on either thymomas or TC, although multikinase inhibitors may have some effect on TC. The current evidence suggests that the most active agent is lenvatinib, whereas sunitinib could be proposed as an acceptable second-line therapy for TC. Further research concerning the combination of immune checkpoint inhibitors with anti-angiogenic drugs is warranted.

A combined intrapleural administration of dornase alfa and tissue plasminogen activator is safe in children with empyema - A pilot study.

OBJECTIVE: There is still no consensus regarding the treatment of empyema in children. Intrapleural combination of tissue plasminogen activator and dornase alfa is a promising treatment for empyema in adults. The aim of this pilot study was to determine whether this combination is safe and successful in pediatric empyema. METHODS: Previous well children diagnosed with empyema as classified by the British Thoracic Society. After chest tube insertion, intrapleurally dornase alfa 2.5 mg for 2 days and tissue plasminogen activator 0.15 mg/kg for 3 days was given after which the chest tube was clamped for 4 h. Primary outcome was safety. RESULTS: Ten consecutive children were included (4 boys, aged 3.2 (1.3-15.0) years old). No serious adverse events were seen. One child developed urticaria but additional intervention or cessation of the trial was not needed. There was no bleeding or mortality and no additional procedures were performed. The median hospital stay after intervention was 7.5 days. CONCLUSIONS: The intrapleural treatment of dornase alfa and tissue plasminogen activator as treatment of empyema was safe in ten children with empyema. If confirmed in further studies, this combination of intrapleural therapy may improve the management of pediatric empyema.

Myasthenia gravis appearing after thymectomy heralding recurrent thymoma.

INTRODUCTION: Thirty to fifty percent of thymoma patients develop myasthenia gravis (MG). In 1.5-28% of cases, MG appears many years after removal of a thymoma. PATIENTS AND METHODS: We present a case report of a 72-year-old female who presented with MG four months after total thymectomy. RESULTS: A 72-year-old female patient presents with MG four months after total thymectomy. Imaging revealed a PET-positive nodule anterior to the superior vena cava. By median sternotomy, the nodule was removed at our hospital. Pathology confirmed a recurrent B2/B3 thymoma with R0 resection. No adjuvant therapy was given. Large population studies show the appearance of new-onset MG associated with recurrent thymoma in 3% of cases. CONCLUSIONS: New-onset MG postthymectomy heralds recurrent disease in 3% of cases. Thorough screening is needed in such patients.

MEDIASTinal staging of non-small cell lung cancer by endobronchial and endoscopic ultrasonography with or without additional surgical mediastinoscopy (MEDIASTrial): study protocol of a multicenter randomised controlled trial.

BACKGROUND: In case of suspicious lymph nodes on computed tomography (CT) or fluorodeoxyglucose positron emission tomography (FDG-PET), advanced tumour size or central tumour location in patients with suspected non-small cell lung cancer (NSCLC), Dutch and European guidelines recommend mediastinal staging by endosonography (endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS)) with sampling of mediastinal lymph nodes. If biopsy results from endosonography turn out negative, additional surgical staging of the mediastinum by mediastinoscopy is advised to prevent unnecessary lung resection due to false negative endosonography findings. We hypothesize that omitting mediastinoscopy after negative endosonography in mediastinal staging of NSCLC does not result in an unacceptable percentage of unforeseen N2 disease at surgical resection. In addition, omitting mediastinoscopy comprises no extra waiting time until definite surgery, omits one extra general anaesthesia and hospital admission, and may be associated with lower morbidity and comparable survival. Therefore, this strategy may reduce health care costs and increase quality of life. The aim of this study is to compare the cost-effectiveness and cost-utility of mediastinal staging strategies including and excluding mediastinoscopy. METHODS/DESIGN: This study is a multicenter parallel randomized non-inferiority trial comparing two diagnostic strategies (with or without mediastinoscopy) for mediastinal staging in 360 patients with suspected resectable NSCLC. Patients are eligible for inclusion when they underwent systematic endosonography to evaluate mediastinal lymph nodes including tissue sampling with negative endosonography results. Patients will not be eligible for inclusion when PET/CT demonstrates 'bulky N2-N3' disease or the combination of a highly suspicious as well as irresectable mediastinal lymph node. Primary outcome measure for non-inferiority is the proportion of patients with unforeseen N2 disease at surgery. Secondary outcome measures are hospitalization, morbidity, overall 2-year survival, quality of life, cost-effectiveness and cost-utility. Patients will be followed up 2 years after start of treatment. DISCUSSION: Results of the MEDIASTrial will have immediate impact on national and international guidelines, which are accessible to public, possibly reducing mediastinoscopy as a commonly performed invasive procedure for NSCLC staging and diminishing variation in clinical practice. TRIAL REGISTRATION: The trial is registered at the Netherlands Trial Register on July 6th, 2017 ( NTR 6528 ).

Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017.

The Fleischner Society Guidelines for management of solid nodules were published in 2005, and separate guidelines for subsolid nodules were issued in 2013. Since then, new information has become available; therefore, the guidelines have been revised to reflect current thinking on nodule management. The revised guidelines incorporate several substantive changes that reflect current thinking on the management of small nodules. The minimum threshold size for routine follow-up has been increased, and recommended follow-up intervals are now given as a range rather than as a precise time period to give radiologists, clinicians, and patients greater discretion to accommodate individual risk factors and preferences. The guidelines for solid and subsolid nodules have been combined in one simplified table, and specific recommendations have been included for multiple nodules. These guidelines represent the consensus of the Fleischner Society, and as such, they incorporate the opinions of a multidisciplinary international group of thoracic radiologists, pulmonologists, surgeons, pathologists, and other specialists. Changes from the previous guidelines issued by the Fleischner Society are based on new data and accumulated experience. © RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on March 13, 2017.

Intensive care in thoracic oncology.

The admission of lung cancer patients to intensive care is related to postprocedural/postoperative care and medical complications due to cancer or its treatment, but is also related to acute organ failure not directly related to cancer.Despite careful preoperative risk management and the use of modern surgical and anaesthetic techniques, thoracic surgery remains associated with high morbidity, related to the extent of resection and specific comorbidities. Fast-tracking processes with timely recognition and treatment of complications favourably influence patient outcome. Postoperative preventive and therapeutic management has to be carefully planned in order to reduce postoperative morbidity and mortality.For patients with severe complications, intensive care unit (ICU) mortality rate ranges from 13% to 47%, and hospital mortality ranges from 24% to 65%. Common predictors of in-hospital mortality are severity scores, number of failing organs, general condition, respiratory distress and the need for mechanical ventilation or vasopressors. When considering long-term survival after discharge, cancer-related parameters retain their prognostic value.Thoracic surgeons, anesthesiologists, pneumologists, intensivists and oncologists need to develop close and confident partnerships aimed at implementing evidence-based patient care, securing clinical pathways for patient management while promoting education, research and innovation. The final decision on admitting a patient with lung to the ICU should be taken in close partnership between this medical team and the patient and his or her relatives.

Management of stage I and II nonsmall cell lung cancer.

The incidence of stage I and II nonsmall cell lung cancer is likely to increase with the ageing population and introduction of screening for high-risk individuals. Optimal management requires multidisciplinary collaboration. Local treatments include surgery and radiotherapy and these are currently combined with (neo)adjuvant chemotherapy in specific cases to improve long-term outcome. Targeted therapies and immunotherapy may also become important therapeutic modalities in this patient group. For resectable disease in patients with low cardiopulmonary risk, complete surgical resection with lobectomy remains the gold standard. Minimally invasive techniques, conservative and sublobar resections are suitable for a subset of patients. Data are emerging that radiotherapy, especially stereotactic body radiation therapy, is a valid alternative in compromised patients who are high-risk candidates for surgery. Whether this is also true for good surgical candidates remains to be evaluated in randomised trials. In specific subgroups adjuvant chemotherapy has been shown to prolong survival; however, patient selection remains important. Neoadjuvant chemotherapy may yield similar results as adjuvant chemotherapy. The role of targeted therapies and immunotherapy in early stage nonsmall cell lung cancer has not yet been determined and results of randomised trials are awaited.

Malignant pleural mesothelioma: single-institution experience of 101 patients over a 15-year period.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but aggressive neoplasm that typically originates from the mesothelial surfaces of the pleural cavity. Exposure to asbestos is the principal etiological agent of MPM. The disease is characterized by difficult stage classification and limited consensus on therapeutic approach. We have evaluated the experience with MPM in the Antwerp University Hospital over the past 15 years. METHODS: A database was created with all patients diagnosed with or treated for a MPM between 2001 and 2015. A total of 101 patients were included on which different survival analyses were performed combined with a reproduction of demographic, clinical, histologic and therapeutic data, and these were compared to literature data. RESULTS: Vast majority of our 101 patients were male (80%) with a median age of 66 years at diagnosis with predominantly epitheloid histology (81%). Overall median survival was 18.3 months and overall 1-, 2- and 5-year survival rates were 68%, 37% and 7%, respectively. Kaplan-Meier analysis showed a non-significant difference in survival between the several best (b) TNM-stages (p = .356). A significant difference in survival was observed in patients undergoing surgery versus no surgery (p = .008), between the different histological types (p < .0001) and treatment with chemotherapy alone versus chemotherapy with surgery (p < .0001). Smoking at diagnosis and epitheloid histology have been identified as significant prognostic factors in the multivariate Cox regression model (HR 3.13 and 0.53, respectively). CONCLUSION: Descriptive and survival analysis of our patient database confirmed the limitations of the current staging system and were concordant with literature regarding MPM.

Diagnostic procedures for non-small-cell lung cancer (NSCLC): recommendations of the European Expert Group.

BACKGROUND: There is currently no Europe-wide consensus on the appropriate preanalytical measures and workflow to optimise procedures for tissue-based molecular testing of non-small-cell lung cancer (NSCLC). To address this, a group of lung cancer experts (see list of authors) convened to discuss and propose standard operating procedures (SOPs) for NSCLC. METHODS: Based on earlier meetings and scientific expertise on lung cancer, a multidisciplinary group meeting was aligned. The aim was to include all relevant aspects concerning NSCLC diagnosis. After careful consideration, the following topics were selected and each was reviewed by the experts: surgical resection and sampling; biopsy procedures for analysis; preanalytical and other variables affecting quality of tissue; tissue conservation; testing procedures for epidermal growth factor receptor, anaplastic lymphoma kinase and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) in lung tissue and cytological specimens; as well as standardised reporting and quality control (QC). Finally, an optimal workflow was described. RESULTS: Suggested optimal procedures and workflows are discussed in detail. The broad consensus was that the complex workflow presented can only be executed effectively by an interdisciplinary approach using a well-trained team. CONCLUSIONS: To optimise diagnosis and treatment of patients with NSCLC, it is essential to establish SOPs that are adaptable to the local situation. In addition, a continuous QC system and a local multidisciplinary tumour-type-oriented board are essential.

Linking CD11b (+) Dendritic Cells and Natural Killer T Cells to Plaque Inflammation in Atherosclerosis.

Atherosclerosis remains the leading cause of death and disability in our Western society. To investigate whether the dynamics of leukocyte (sub)populations could be predictive for plaque inflammation during atherosclerosis, we analyzed innate and adaptive immune cell distributions in blood, plaques, and lymphoid tissue reservoirs in apolipoprotein E-deficient (ApoE(-/-)) mice and in blood and plaques from patients undergoing endarterectomy. Firstly, there was predominance of the CD11b(+) conventional dendritic cell (cDC) subset in the plaque. Secondly, a strong inverse correlation was observed between CD11b(+) cDC or natural killer T (NKT) cells in blood and markers of inflammation in the plaque (including CD3, T-bet, CCR5, and CCR7). This indicates that circulating CD11b(+) cDC and NKT cells show great potential to reflect the inflammatory status in the atherosclerotic plaque. Our results suggest that distinct changes in inflammatory cell dynamics may carry biomarker potential reflecting atherosclerotic lesion progression. This not only is crucial for a better understanding of the immunopathogenesis but also bares therapeutic potential, since immune cell-based therapies are emerging as a promising novel strategy in the battle against atherosclerosis and its associated comorbidities. The cDC-NKT cell interaction in atherosclerosis serves as a good candidate for future investigations.

Solitary fibrous tumor of the pleura with associated Doege-Potter syndrome.

Doege-Potter syndrome is a paraneoplastic syndrome characterized by tumor-associated hypoglycemia secondary to a solitary fibrous tumor of the pleura. We present a case of an 84-year-old man, who presented with acute mental confusion and therapy-resistant hypoglycemia. Diagnostic imaging revealed a large sharply defined pleural tumor based on the left diaphragm, after surgical resection the diagnosis was made of a malignant solitary fibrous tumor of the pleura and restoration of the glucose homeostasis was observed.

A murine model of lung ischemia and reperfusion injury: tricks of the trade.

BACKGROUND: Pulmonary ischemia-reperfusion injury (IRI) causes postoperative morbidity in patients undergoing lung transplantation, isolated lung perfusion, and cardiopulmonary bypass and may lead to potentially lethal pathologies such as respiratory shock. In-depth study of this pathology requires a reliable animal model. Mice are a popular species to develop experimental models because of their logistic advantages and the availability of knock outs. However, their small size warrants microsurgical techniques and a skilled surgeon. MATERIALS AND METHODS: We developed a murine model of pulmonary anoxic IRI through hilar clamping using adult female Swiss mice. After left thoracotomy, we expose the pulmonary hilum keeping the ribs and the muscles of back and forepaw intact. A microvascular clamp is placed over the entire hilum, occluding bronchus, pulmonary artery, and vein. RESULTS: Our model proved to be simple, reliable, and reproducible, showing minimal preoperative and postoperative mortality. Histopathologic analysis indicated all characteristic features of pulmonary IRI, such as an early recruitment of lymphocytes followed by neutrophil influx. CONCLUSIONS: This article presents a murine surgery model for pulmonary IRI based on a muscle-sparing thoracotomy. The minimal approach limits manipulation of lung tissue, minimizing mortality and non-IRI-induced injury.

Multimodal management of malignant pleural mesothelioma: where are we today?

The prognosis of patients with malignant pleural mesothelioma remains poor and although it is clear that multimodal therapy is necessary to improve long-term results, precise treatment schemes have not yet been unequivocally established. Single-modality therapy does not have a major impact on long-term survival and combined-modality therapies are being further evaluated. However, the relative contributions of chemotherapy, radiotherapy and surgery have not been clearly determined at the present time. Moreover, the extent of resection and precise surgical procedure remain a highly debated topic. To better compare and combine results from different institutions and trials, uniform definitions of surgical procedures including extrapleural pneumonectomy and different forms of pleurectomy have recently been introduced. Due to the relatively higher morbidity and mortality of extrapleural pneumonectomy, there is currently a shift towards pleurectomy/decortication when a macroscopic complete resection of all tumour can be obtained by this procedure. In most recent trials, induction chemotherapy was administered to improve surgical resection rates but pathological complete responses are infrequently observed. The role of post-operative radiotherapy has to be further elucidated. Further treatment options that are currently explored include hyperthermic intrapleural chemotherapy, immunotherapy, gene therapy and photodynamic therapy. However, no randomised comparisons are available yet.

The European initiative for quality management in lung cancer care.

Lung cancer is the commonest cause of cancer-related death worldwide and poses a significant respiratory disease burden. Little is known about the provision of lung cancer care across Europe. The overall aim of the Task Force was to investigate current practice in lung cancer care across Europe. The Task Force undertook four projects: 1) a narrative literature search on quality management of lung cancer; 2) a survey of national and local infrastructure for lung cancer care in Europe; 3) a benchmarking project on the quality of (inter)national lung cancer guidelines in Europe; and 4) a feasibility study of prospective data collection in a pan-European setting. There is little peer-reviewed literature on quality management in lung cancer care. The survey revealed important differences in the infrastructure of lung cancer care in Europe. The European guidelines that were assessed displayed wide variation in content and scope, as well as methodological quality but at the same time there was relevant duplication. The feasibility study demonstrated that it is, in principle, feasible to collect prospective demographic and clinical data on patients with lung cancer. Legal obligations vary among countries. The European Initiative for Quality Management in Lung Cancer Care has provided the first comprehensive snapshot of lung cancer care in Europe.

Surgical treatment of thymic epithelial tumors: a narrative review.

Background and Objective: Thymic epithelial tumors (TETs) are scarce neoplasms of the prevascular mediastinum. Included in this diverse category of lesions are thymomas and thymic carcinomas (TCs). Surgery is the mainstay of treatment of tumors that are deemed resectable. However, up till now, optimal surgical access has been a subject of debate. The advent of new techniques, such as video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS), challenged the median sternotomy which was traditionally considered the access of choice. This review aims to demonstrate the current evidence concerning the surgical treatment of TET and to enlighten other controversial issues about surgery. Methods: PubMed research was conducted using the terms [surgery] AND [thymic epithelial tumors] OR [thymomas] and [surgical treatment] AND [thymic epithelial tumors] OR [thymomas]. Papers concerning pediatric cases and non-English literature papers were excluded. Individual case reports were also excluded. Key Content and Findings: Minimally invasive surgical techniques (MIST) such as VATS and RATS are increasingly applied in early-stage TET. Although numerous published studies have demonstrated better perioperative outcomes in early-stage TET, long-term follow-up data are still required to demonstrate the oncological equivalent of MIST to open surgery. Resection of stage III TET is more challenging. Thymectomy can be expanded en bloc to include the major vascular structures, lung, pleura, phrenic, or vagus nerve in these individuals. There is no agreement on the ideal surgical access and traditionally these patients underwent open sternotomy, sometimes combined with a thoracic access. Evidence concerning the treatment of stage IVA disease is mainly derived from retrospective case series which are highly heterogeneous in terms of the number of enrolled patients, histology, degree of pleural involvement, and timing of presentation. Conclusions: New techniques in the field of minimally invasive surgery are gaining acceptance for early-stage TET but longer follow-up periods are warranted to prove their oncological outcomes. On the contrary, these techniques should be used cautiously in case of locally advanced tumors. Surgeons must not forget that the main objective is the complete resection of the lesion, which is one major predictive factor for increased survival.

The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groups in the Forthcoming (Ninth) Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: The TNM classification of lung cancer is periodically revised. The International Association for the Study of Lung Cancer collected and analyzed a new database to inform the forthcoming ninth edition of the TNM classification. The results are herewith presented. METHODS: After exclusions, 76,518 patients from a total of 124,581 registered patients were available for analyses: 58,193 with clinical stage, 39,192 with pathologic stage, and 62,611 with best stage NSCLC. The proposed new N2 subcategories (N2a, involvement of single ipsilateral mediastinal or subcarinal nodal station, and N2b, involvement of multiple ipsilateral mediastinal nodal stations with or without involvement of the subcarinal nodal station) and the new M1c subcategories (M1c1, multiple extrathoracic metastases in one organ system, and M1c2, multiple extrathoracic metastases in multiple organ systems) were considered in the survival analyses. Several potential stage groupings were evaluated, using multiple analyses, including recursive partitioning, assessment of homogeneity within and discrimination between potential groups, clinical and statistical significance of survival differences, multivariable regression, and broad assessment of generalizability. RESULTS: T1N1, T1N2a, and T3N2a subgroups are assigned to IIA, IIB, and IIIA stage groups, respectively. T2aN2b and T2bN2b subgroups are assigned to IIIB. M1c1 and M1c2 remain in stage group IVB. Analyses reveal consistent ordering, discrimination of prognosis, and broad generalizability of the proposed ninth edition stage classification of lung cancer. CONCLUSIONS: The proposed stages for the ninth edition TNM improve the granularity of nomenclature about anatomic extent that has benefits as treatment approaches become increasingly differentiated and complex.