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.

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.

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.

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.

The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revisions of the T-Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: An international database was created by the International Association for the Study of Lung Cancer to inform on the ninth edition of the TNM classification of lung cancer. The present analyses concern its T component. METHODS: Data on 124,581 patients diagnosed with lung cancer from January 1, 2011 to December 31, 2019 were submitted to the International Association for the Study of Lung Cancer database. Of these, 33,982 met the inclusion criteria for the clinical T analysis, and 30,715 met the inclusion criteria for the pathologic postsurgical analysis. Survival was measured from the date of diagnosis or operation for clinically and pathologically staged tumors, respectively. T descriptors were evaluated in univariate analysis and multivariable Cox regression analysis adjusted for age, sex, pathologic type, and geographic region. RESULTS: Comprehensive survival analysis revealed that the existing eighth edition T component criteria performed adequately in the ninth edition data set. Although pathologic chest wall or parietal pleura involvement (PL 3) yielded a worse survival compared with the other T3 descriptors, with a similar survival as T4 tumors, this difference was not observed for clinical chest wall or PL 3 tumors. Because of these inconsistent findings, no reallocation of chest wall or PL 3 tumors is advised. CONCLUSIONS: The T subcommittee members proposed not to implement any changes and keep the current eighth-edition T descriptors for the ninth edition.

True Prevalence of Unforeseen N2 Disease in NSCLC: A Systematic Review + Meta-Analysis.

Patients with unforeseen N2 (uN2) disease are traditionally considered to have an unfavorable prognosis. As preoperative and intraoperative mediastinal staging improved over time, the prevalence of uN2 changed. In this review, the current evidence on uN2 disease and its prevalence will be evaluated. A systematic literature search was performed to identify all studies or completed, published trials that included uN2 disease until 6 April 2023, without language restrictions. The Newcastle-Ottawa Scale (NOS) was used to score the included papers. A total of 512 articles were initially identified, of which a total of 22 studies met the predefined inclusion criteria. Despite adequate mediastinal staging, the pooled prevalence of true unforeseen pN2 (9387 patients) was 7.97% (95% CI 6.67-9.27%), with a pooled OS after five years (892 patients) of 44% (95% CI 31-58%). Substantial heterogeneity regarding the characteristics of uN2 disease limited our meta-analysis considerably. However, it seems patients with uN2 disease represent a subcategory with a similar prognosis to stage IIb if complete surgical resection can be achieved, and the contribution of adjuvant therapy is to be further explored.

Innovative Invasive Loco-Regional Techniques for the Treatment of Lung Cancer.

Surgical resection is still the standard treatment for early-stage lung cancer. A multimodal treatment consisting of chemotherapy, radiotherapy and/or immunotherapy is advised for more advanced disease stages (stages IIb, III and IV). The role of surgery in these stages is limited to very specific indications. Regional treatment techniques are being introduced at a high speed because of improved technology and their possible advantages over traditional surgery. This review includes an overview of established and promising innovative invasive loco-regional techniques stratified based on the route of administration, including endobronchial, endovascular and transthoracic routes, a discussion of the results for each method, and an overview of their implementation and effectiveness.

Sublobar Resection for Early-Stage Lung Cancer: An Oncologically Valid Procedure?

In the era of minimally invasive surgery, the role of sublobar resection comprising anatomical segmentectomy and wide wedge excision remains controversial [...].

Good's syndrome and COVID-19: case report and literature review.

Background: Good's syndrome (GS) is an adult-onset acquired immunodeficiency, in which patients present with thymoma and hypogammaglobulinemia (HGG). GS is characterized by low to absent peripheral B cells and impaired T-cell mediated immunity, often resulting in various (opportunistic) infections and concurrent autoimmune disorders. In this case report, we present a case of a patient with GS and coronavirus disease 2019 (COVID-19) infection after surgical removal of a thymoma. The simultaneous occurence of these two entities is extremely rare. Case Description: A 55-year-old man presented with oral lichen planus and cutaneous lesions. Additional symptoms included a weight loss of 5 kilograms in the last six months. Computed tomography (CT) and positron emission tomography (PET) of the chest showed a large anterior mediastinal mass with a maximum diameter of 10 centimetres. A core needle biopsy was performed, which led to a pathological diagnosis of thymoma type AB. In addition to these earlier findings, laboratory analysis revealed HGG. The combination of a thymoma and HGG led to a diagnosis of GS. Induction chemotherapy with cisplatin-etoposide was started, however, the patient developed COVID-19 after 2 cycles. Treatment with remdesivir was initiated and, subsequently, a thymectomy via sternotomy was performed. Final pathology confirmed a thymoma type AB of 14 centimetres, fully encapsulated, and without invasion. Resection margins were negative and the tumour was classified as pT1aN0, R0 resection. The patient has received immunoglobulin treatments every 4 weeks for his GS and has not developed any new infections since the start of this therapy. Conclusions: Patients with GS are prone to developing (pulmonary) infections. Clinicians should be aware of the possible clinical effects of COVID-19 infections in this patient population.

Tumor Microenvironment in Thymic Epithelial Tumors: A Narrative Review.

The tumor microenvironment (TME) is a complex and constantly changing entity. The TME consists of stromal cells, fibroblasts, endothelial cells, and innate and adaptive immune cells. Cancer development and progression occurs through this interplay between the tumor and the adjacent stroma. Cancer cells are capable of modifying their microenvironment by secreting various message-carrying molecules, such as cytokines, chemokines, and other factors. This action causes a reprogramming of the neighboring cells, which are enabled to play a crucial role in tumor survival and progression. The study of TME has many clinical implications in terms of cancer therapeutics because many new drugs, such as antibodies, kinase inhibitors, and liposome formulations that can encapsulate anti-cancer drugs, can be developed. Although chemotherapy is considered the standard of treatment for advanced disease, recent research has brought to light immunotherapy as a possible systemic alternative. However, the complex structure and function of the thymus hinders its routine use in clinical practice. The aim of this review paper is to discuss the recent advances in the investigation of the unique characteristics of the TME of thymic epithelial tumors that could possibly lead to the development of novel promising therapies.

Prognostic factors and genetic markers in thymic epithelial tumors: A narrative review.

Thymic epithelial tumors (TET) are a group of rare neoplasms of the anterior mediastinum comprising thymomas and thymic carcinomas. The carcinogenesis of TET is mostly unknown. Many studies, mostly retrospective case series, have tried to establish prognostic factors in TET. TET is a very heterogeneous group of tumors with many subtypes for which diagnosis and treatment remains a very challenging task. Despite the disparities among retrospective studies, there are some prognostic factors that are more pertinent such as the completeness of resection, TNM stage and the Masaoka-Koga classification. On the other hand, the identification of different genetic pathways that result in the pathogenesis of TET represents a fascinating field of study that could possibly lead to the development of new targeted therapies. The aim of this review is to discuss the different prognostic factors and genetic markers of TET. The meticulous use of national and international databases could provide sufficient number of patients in order to draw more valid conclusions.

How Can the EU Beating Cancer Plan Help in Tackling Lung Cancer, Colorectal Cancer, Breast Cancer and Melanoma?

Cancer is the second leading cause of mortality in EU countries, and the needs to tackle cancer are obvious. New scientific understanding, techniques and methodologies are opening up horizons for significant improvements in diagnosis and care. However, take-up is uneven, research needs and potential outstrip currently available resources, manifestly beneficial practices-such as population-level screening for lung cancer-are still not generalised, and the quality of life of patients and survivors is only beginning to be given attention it merits. This paper, mainly based on a series of multistakeholder expert workshops organised by the European Alliance for Personalised Medicine (EAPM), looks at some of those specifics in the interest of planning a way forward. Part of this exercise also involves taking account of the specific nature of Europe and its constituent countries, where the complexities of planning a way forward are redoubled by the wide variations in national and regional approaches to cancer, local epidemiology and the wide disparities in health systems. Despite all the differences between cancers and national and regional resources and approaches to cancer care, there is a common objective in pursuing broader and more equal access to the best available care for all European citizens.

Clinical characteristics, surgical treatments, prognosis, and prognostic factors of primary tracheal cancer patients: 20-year data of the National Cancer Center, China.

Background: Tracheal cancer is a rare malignancy of which previous reports are mostly case reports or small series. Herein, we sought to evaluate the clinical characteristics, surgical treatments, and prognosis of surgically treated primary tracheal cancer patients. Methods: Patients with primary tracheal cancer who had received surgery in our center between January 2000 and December 2020 were enrolled. Clinical and surgical features were collected by retrospective review of medical records and follow-up was done by telephone interview. The statistical tests were two-sided. Results: A total of 128 patients were included in the study, 49.2% of whom were male, and the average age was 49.4±13.6 years. The most common histological subtype was adenoid cystic carcinoma (ACC; 78/128, 60.9%) followed by squamous cell carcinoma (SCC; 24/128, 18.8%). The percentage of tumors located in the cervical trachea, thoracic trachea, and carina were 50%, 41.4%, and 8.6%, respectively. Among those analyzed, 32.0% of the primary tumors had invaded adjacent organs (E2 disease) and 7.8% of patients had lymph node involvement. Tracheal resection plus reconstruction (with or without thyroidectomy) was the predominant surgical procedure, followed by carinal resection with neocarina. Radical resection (R0) was performed on 61.7% of patients and 63 (49.2%) patients received adjuvant therapy. Compared to ACC, SCC patients had significantly higher risk of tumor of the carina, nodal metastasis, and complications. The 5-year overall survival (OS) for the entire cohort was 84.5% and factors associated with poor prognosis included carinal tumor [hazard ratio (HR) =10.206; P<0.001], E2 disease (HR =8.870; P=0.001), lymph node metastasis (HR =15.197; P<0.001), and postoperative complications (HR =12.497; P=0.001). Conclusions: The two major subtypes of tracheal cancer are ACC and SCC. Tumor location, extension, lymph node metastasis and complication are survival related factors for surgically treated patients.

From Macroscopy to Ultrastructure: An Integrative Approach to Pulmonary Pathology.

Pathology and radiology are complimentary tools, and their joint application is often crucial in obtaining an accurate diagnosis in non-neoplastic pulmonary diseases. However, both come with significant limitations of their own: Computed Tomography (CT) can only visualize larger structures due to its inherent-relatively-poor resolution, while (histo) pathology is often limited due to small sample size and sampling error and only allows for a 2D investigation. An innovative approach of inflating whole lung specimens and subjecting these subsequently to CT and whole lung microCT allows for an accurate matching of CT-imaging and histopathology data of exactly the same areas. Systematic application of this approach allows for a more targeted assessment of localized disease extent and more specifically can be used to investigate early mechanisms of lung diseases on a morphological and molecular level. Therefore, this technique is suitable to selectively investigate changes in the large and small airways, as well as the pulmonary arteries, veins and capillaries in relation to the disease extent in the same lung specimen. In this perspective we provide an overview of the different strategies that are currently being used, as well as how this growing field could further evolve.

Multimodality Treatment including Surgery Related to the Type of N2 Involvement in Locally Advanced Non-Small Cell Lung Cancer.

For patients with locally advanced non-small cell lung cancer (NSCLC) or positive N1 nodes, multimodality treatment is indicated. However, the optimal management of patients presenting with ipsilateral positive mediastinal nodes (N2 disease) has not been determined yet. Different treatment regimens consisting of chemotherapy, radiation therapy, and surgery have been proposed and implemented previously. In more recent years, immunotherapy and targeted therapies have been added as therapeutic options. The role of surgery is currently redefined. Recent studies have shown that surgical resection after induction immunotherapy or targeted therapy is feasible and yields good short-term results. In this review, we summarize the latest data on multimodality treatment options for stage IIIA-N2 locally advanced NSCLC, depending on the extent of nodal involvement.