Pleural mesothelioma: is the surgeon still there?

Malignant pleural mesothelioma (MPM) is a rare malignancy with some unique characteristics. Tumor biology is aggressive and prognosis is poor. Despite more knowledge on histology, tumor biology and staging, there is still a relevant discrepancy between clinical and pathologic staging resulting in difficult prediction of prognosis and treatment outcome, making treatment allocation more challenging than in most other malignancies. After years of nihilism in the late 80s, a period of activism started evaluating different treatment protocols combined with research driven mainly by academic centers; at the time, selection was based on histology and stage only. This period was important to gain knowledge about the disease. However, the interpretation of data was difficult since selection criteria and definitions varied substantially. Not surprisingly, until now there is no common agreement on best treatment even among specialists. Hence, a review of our current concepts is indicated and personalized treatment should become applicable in the future. Surgery was and still is an issue of debate. In principle, surgery is an effective approach as it allows macroscopic complete elimination of a tumor, which is relatively resistant to medical treatment. It helps to set the clock back and other therapies that have also just a limited effect can be applied sequentially before or after surgery. Furthermore, to date best long-term outcome is reported from surgical series in combination with other modalities. However, part of the community considers surgery associated with too high morbidity and mortality when balanced to the limited life expectancy. This criticism is understandable, since poor results after surgery are reported. The present article will review the indication for surgery and discuss the different procedures available for macroscopic complete resection-such as lung-preserving (extended) pleurectomy/decortication as well as extrapleural pneumonectomy to illustrate that 'The surgeon is still there!'

Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project.

Background: Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Methods: Clinically annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test. Results: Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases. Conclusion: Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

[Lung Volume Reduction Surgery]. / Chirurgische Lungenvolumenreduktion.

Lung volume reduction surgery (LVRS) offers improvement in lung function, quality of life and even survival in well selected patients with severe emphysema. Patients with all types of emphysema morphology can profit from LVRS when certain selection criteria are present. Hyperinflation plays a key role in qualifying for the procedure. Candidate selection should be performed at high volume centers with a multidisciplinary emphysema board. Qualified thoracic surgeons together with pulmonologists and radiologists identify the suitable patient considering emphysema morphology with its target areas for resection, lung function parameters and cardiac comorbidities. This review outlines candidate selection, technique and results of LVRS to inform referring physicians how to screen und inform their patients.

[Lung Volume Reduction Surgery - State of the Art 2016]. / Emphysemchirurgie - State of the Art 2016.

In a number of large case series in the mid-1990s, lung volume reduction surgery (LVRS) was shown to reduce dyspnoea and improve pulmonary function and quality of life in patients with advanced pulmonary emphysema. The large randomised National Emphysema Treatment Trial (NETT) confirmed this in the early 2000s and also demonstrated that selected patients live longer after surgery. Patient selection is crucial to the success of the procedure and should be performed at a specialised experienced centre with a multidisciplinary team approach on emphysema treatment. The upper-lobe predominant heterogeneous type of emphysema is the best indication, but there are other types of emphysema morphology that are also eligible for surgery, if ideally chosen. Nowadays there is also growing evidence for positive effects after different types of bronchoscopic lung volume reduction (BLVR) with increasing quality. These methods add to the range of multimodal emphysema treatment.

Searching for targets for the systemic therapy of mesothelioma.

Malignant mesothelioma is an incurable disease associated with asbestos exposure arising in the pleural cavity and less frequently in the peritoneal cavity. Platinum-based combination chemotherapy with pemetrexed is the established standard of care. Multimodality approaches including surgery and radiotherapy are being investigated. Increasing knowledge about the molecular characteristics of mesothelioma had led to the identification of novel potential targets for systemic therapy. Current evidence suggests pathways activated in response to merlin deficiency, including Pi3K/mTOR and the focal adhesion kinase, as well as immunotherapeutic approaches to be most promising. This review elaborates on the rationale behind targeted approaches that have been and are undergoing exploration in mesothelioma and summarizes available clinical results and ongoing efforts to improve the systemic therapy of mesothelioma.

2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on locally advanced disease.

CD74: a new prognostic factor for patients with malignant pleural mesothelioma.

BACKGROUND: The pro-inflammatory cytokine migration inhibitory factor (MIF) and its receptor CD74 have been proposed as possible therapeutic targets in several cancers. We studied the expression of MIF and CD74 together with calretinin in specimens of malignant pleural mesothelioma (MPM), correlating their expression levels with clinico-pathologic parameters, in particular overall survival (OS). METHODS: Migration inhibitory factor, CD74, and calretinin immunoreactivity were investigated in a tissue microarray of 352 patients diagnosed with MPM. Protein expression intensities were semiquantitatively scored in the tumour cells and in the peritumoral stroma. Markers were matched with OS, age, gender, and histological subtype. RESULTS: Clinical data from 135 patients were available. Tumour cell expressions of MIF and CD74 were observed in 95% and 98% of MPM specimens, respectively, with a homogenous distribution between the different histotypes. CD74 (P<0.001) but not MIF overexpression (P=0.231) emerged as an independent prognostic factor for prolonged OS. High expression of tumour cell calretinin correlated with the epithelioid histotype and was also predictive of longer OS (P<0.001). When compared with previously characterised putative epithelial-to-mesenchymal transition markers, CD74 correlated positively with tumoral PTEN and podoplanin expressions, but was inversely related with periostin expression. CONCLUSIONS: High expression of CD74 is an independent prognostic factor for prolonged OS in mesothelioma patients.

Early detection of lung cancer: a statement from an expert panel of the Swiss university hospitals on lung cancer screening.

The discussion about setting up a program for lung cancer screening was launched with the publication of the results of the National Lung Screening Trial, which suggested reduced mortality in high-risk subjects undergoing CT screening. However, important questions about the benefit-harm balance and the details of a screening program and its cost-effectiveness remain unanswered. A panel of specialists in chest radiology, respiratory medicine, epidemiology, and thoracic surgery representing all Swiss university hospitals prepared this joint statement following several meetings. The panel argues that premature and uncontrolled introduction of a lung cancer screening program may cause substantial harm that may remain undetected without rigorous quality control. This position paper focuses on the requirements of running such a program with the objective of harmonizing efforts across the involved specialties and institutions and defining quality standards. The underlying statement includes information on current evidence for a reduction in mortality with lung cancer screening and the potential epidemiologic implications of such a program in Switzerland. Furthermore, requirements for lung cancer screening centers are defined, and recommendations for both the CT technique and the algorithm for lung nodule assessment are provided. In addition, related issues such as patient management, registry, and funding are addressed. Based on the current state of the knowledge, the panel concludes that lung cancer screening in Switzerland should be undertaken exclusively within a national observational study in order to provide answers to several critical questions before considering broad population-based screening for lung cancer.

The technique of orthotopic mouse lung transplantation as a movie-improved learning by visualization.

The introduction of the mouse model of orthotopic single-lung transplantation has significantly advanced research in experimental lung transplantation. Technically, this model is demanding and presents major challenges to the researcher. In order to facilitate and accelerate the successful acquisition of this technique, we provide here a narrated movie in which the full transplantation procedure is comprehensively illustrated, featuring all key operative steps, but also highlighting potential pitfalls.

Advances in surgery.

In the last decade, technological advances, new staging tools, better understanding the role of surgery within multimodal treatment concepts in advanced stages and progress in the functional assessment of surgical candidates improved the quality of surgery in the management of patients with lung cancer. Lung resection with video-assisted thoracoscopic access gained wide acceptance, the indication for lobectomy or sublobar resection in early stages was applied based on new data and selection for multimodal treatment in stage III is better understood based on the data. a major impact on the outcome of patients with lung cancer has the treatment in specialized high-volume centers.

[Malignant pleural mesothelioma]. / Diagnostik und Therapie des malignen Pleuramesothelioms - von der Palliationzur kurativen Intention.

Malignant pleural mesothelioma continues to be a clinical challenge and its incidence will continue to increase worldwide. Once diagnosed with pleural mesothelioma, patients nearly invariably die of the disease. While the benefit of chemotherapy for advanced disease has been established, many other aspects of treatment continue to be controversial, in particular in regard to surgery and radiotherapy. However, the best survival data is reported from groups using multimodality treatment including surgery for patients qualifying from a tumor stage - and functional perspective. Therefore, efforts should focus on improving staging systems. Translational studies should be included with the final aim of finding reliable markers for response to therapy. Despite both, the increase in basic biologic knowledge and the fact that many new agents have reached various stages of development, the number of new treatments that have been approved for patients has not increased. As mesothelioma is a rare disease, the number of patients is limiting and more innovative trial designs (such as multi-arm multi-stage trials [1]) using cooperative platforms to eliminate less effective treatments may be the best way forward.

[Minimal-invasive surgery for lung cancer - strategies and limits]. / Minimal-invasive Chirurgie beim Bronchuskarzinom - Möglichkeit und Limiten.

Minimal invasive surgical procedures, also known as keyhole surgery, have gained in importance in the last years and have become the standard of care in experienced hands for most surgical procedures. Despite initial concerns with respect to the radicalness of the approach it is nowadays also established in oncologic surgery. Minimal invasive procedures aim at minimizing the operative trauma and associated inflammatory reactions to achieve faster convalescence after surgery. In addition to obvious cosmetic advantages minimal invasive surgery has been shown to be associated with fewer postoperative pain and shorter postoperative rehabilitation and faster reintegration into everyday as well as working life. With 15% of all cancer diagnoses and 29% of all cancer-associated causes of death, lung cancer is the most frequent malignancy in the general public and hence the treatment of lung cancer is a main focus of thoracic surgery. Within the scope of modern multimodal treatment concepts radical surgical resection of lung cancer is essential and the main pillar of curative treatment. In early stage lung cancer the current standard of care is a thoracoscopic lobectomy with mediastinal lymphadenectomy. The expertise of specialized centers allows for curative minimal-invasive treatment in a large number of patients, particularly of patients of advanced age or with limited pulmonary function.

Smoking prevention intervention with school classes in university hospital by thoracic surgeon und pulmonologist. The Zurich prevention project.

Smoking prevention in schoolchildren to inform and prevent smoking initiation has been widely studied; however, the potential effect of interventions provided in a hospital setting is unknown. An intervention program named "Schoolchildren smoking prevention in the hospital" was developed in which the health aspects of smoking and its individual consequences were presented in an interactive informational event provided by a thoracic surgeon and a pulmonologist. We aimed to assess the feasibility and the short-term effect of smoking-related knowledge improvement in schoolchildren in a hospital setting. Scholars of 45 classes in Canton of Zurich in Switzerland filled in an anonymous 5-item questionnaire with questions on general knowledge about smoking. The answers were evaluated in this prospective observational cohort study. The primary endpoint was to compare the knowledge improvement by interpretation of answers before-and-after the smoking prevention intervention. Additionally, the performance of children was compared after setting up an overall score and specific subgroups according to gender and school-level. Between Jan 2010, and Oct 2019, schoolchildren aged 10 to 16 years participated in this intervention program and completed the questionnaire before (N = 1270) and after (N = 1264) the intervention. The amount of correctly answered questions increased from 40% (±20) before to 81% (±17), p < 0·0001 after the educational session. An intervention program on health effects of smoking provided by lung specialists in the hospital is feasible, well received, leads to a substantial increase of knowledge, and hopefully can be further explored in the development of smoking prevention programs for schoolchildren.

Long-term outcomes of operable stage III NSCLC in the pre-immunotherapy era: results from a pooled analysis of the SAKK 16/96, SAKK 16/00, SAKK 16/01, and SAKK 16/08 trials.

BACKGROUND: Chemoradiotherapy with durvalumab consolidation has yielded excellent results in stage III non-small-cell lung cancer (NSCLC). Therefore, it is essential to identify patients who might benefit from a surgical approach. MATERIAL AND METHODS: Data from 437 patients with operable stage III NSCLC enrolled in four consecutive Swiss Group for Clinical Cancer Research (SAKK) trials (16/96, 16/00, 16/01, 16/08) were pooled and outcomes were analyzed in 431 eligible patients. All patients were treated with three cycles of induction chemotherapy (cisplatin/docetaxel), followed in some patients by neoadjuvant radiotherapy (44 Gy, 22 fractions) (16/00, 16/01, 16/08) and cetuximab (16/08). RESULTS: With a median follow-up time of 9.3 years (range 8.5-10.3 years), 5- and 10-year overall survival (OS) rates were 37% and 25%, respectively. Overall, 342 patients (79%) underwent tumor resection, with a complete resection (R0) rate of 80%. Patients (n = 272, 63%) with R0 had significantly longer OS compared to patients who had surgery but incomplete resection (64.8 versus 19.2 months, P < 0.001). OS for patients who achieved pathological complete remission (pCR) (n = 66, 15%) was significantly better compared to resected patients without pCR (86.5 versus 37.0 months, P = 0.003). For patients with pCR, the 5- and 10-year event-free survival and OS rates were 45.7% [95% confidence interval (CI) 32.8% to 57.7%] and 28.1% (95% CI 15.2% to 42.6%), and 58.2% (95% CI 45.2% to 69.2%) and 45.0% (95% CI 31.5% to 57.6%), respectively. CONCLUSION: We report favorable long-term outcomes in patients with operable stage III NSCLC treated with neoadjuvant chemotherapy with cisplatin and docetaxel ± neoadjuvant sequential radiotherapy from four prospective SAKK trials. Almost two-third of the patients underwent complete resection after neoadjuvant therapy. We confirm R0 resection and pCR as important predictors of outcome.

Volumetry: an alternative to assess therapy response for malignant pleural mesothelioma?

The purpose of our study was to assess robustness of volumetric measurement of malignant pleural mesothelioma (MPM) before and after chemotherapy to modified RECIST (response evaluation criteria in solid tumours) criteria. 30 patients with digitally available chest computed tomography (CT) scans before and after three cycles of chemotherapy were included. Three readers independently assessed tumour response using two different methods: 1) the modified RECIST criteria; and 2) the tumour volumetric approach using dedicated software (Myrian; Intrasense, Paris, France). Inter-rater reliability of unidimensional and volumetric measurements was assessed using intraclass correlation. Tumour response classification for modified RECIST was compared to the volumetric approach applying unidimensional RECIST volumetric equivalent criteria. The determination of unidimensional tumour measurement (RECIST) revealed a low inter-rater reliability (0.55) and a low interobserver agreement for tumour response classification (general κ 0.33). Only 14 patients were classified equally. A high inter-rater reliability (0.99) and interobserver agreement (general κ 0.9) were found for absolute tumour volumes (volumetric measurements). 27 cases were classified equally. The number of cases classified as "stable disease" was higher for the volumetric approach using tumour-equivalent criteria compared to modified RECIST. Volumetric measurement of MPM on CT using Myrian software is a reliable, reproducible and sensitive method to measure tumour volume and, thus, therapy response after induction chemotherapy.

A model of chronic lung allograft rejection in the rat.

Bronchiolitis obliterans, the pathological hallmark of chronic pulmonary rejection, severely impacts long-term survival following lung transplantation. However, experimental reproduction of this pathophysiological phenomenon has not been achieved with contemporary in vivo models. Here, a model of chronic rejection is described, with sensitised recipients receiving unilateral orthotopic rat lung transplants. Lewis rats, sensitised with skin from brown Norway rats 7 days before receiving left lung transplants from donors that were Lewis x brown Norway F(1) hybrids, were analysed during day 21-84. The development of chronic rejection was modulated by a treatment with rapamycin and cyclosporin, and characterised histologically, immunohistochemically and by reverse transcriptase PCR. Characteristic histopathological changes leading to chronic rejection were induced over time by an initial treatment with cyclosporin in the presence of continuous rapamycin application. At day 84, fibrotic lesions replaced the respiratory epithelium within small bronchioles, with strong expression of smooth muscle alpha-actin and upregulation of mRNA for T-helper cell type-1 cytokines, smooth muscle alpha-actin, transforming growth factor-beta and CC chemokine ligand 5, but decreased forkhead box protein P3 gene expression. A reproducible and clinically relevant experimental set-up for progressive chronic rejection in rat pulmonary allografts is described. This model will permit better understanding of the pathological changes of small airways during the development of bronchiolitis obliterans, and may serve as an in vivo set-up for testing the efficacy of novel therapeutic interventions.

Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare tumour but with increasing incidence and a poor prognosis. In 2008, the European Respiratory Society/European Society of Thoracic Surgeons Task Force brought together experts to propose practical and up-to-dated guidelines on the management of MPM. To obtain an earlier and reliable diagnosis of MPM, the experts recommend performing thoracoscopy, except in cases of pre-operative contraindication or pleural symphysis. The standard staining procedures are insufficient in approximately 10% of cases. Therefore, we propose using specific immunohistochemistry markers on pleural biopsies. In the absence of a uniform, robust and validated staging system, we advice use of the most recent TNM based classification, and propose a three step pre-treatment assessment. Patient's performance status and histological subtype are currently the only prognostic factors of clinical importance in the management of MPM. Other potential parameters should be recorded at baseline and reported in clinical trials. MPM exhibits a high resistance to chemotherapy and only a few patients are candidates for radical surgery. New therapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach should be included in a prospective trial at a specialised centre.