Brain-derived neurotrophic factor, a new soluble biomarker for malignant pleural mesothelioma involved in angiogenesis.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The discovery of soluble biomarkers with diagnostic/prognostic and/or therapeutic properties would improve therapeutic care of MPM patients. Currently, soluble biomarkers described present weaknesses preventing their use in clinic. This study aimed at evaluating brain-derived neurotrophic factor (BDNF), we previously identified using transcriptomic approach, in MPM. We observed that high BDNF expression, at the mRNA level in tumors or at the protein level in pleural effusions (PE), was a specific hallmark of MPM samples. This protein presented significant but limited diagnostic properties (area under the curve (AUC) = 0.6972, p < 0.0001). Interestingly, high BDNF gene expression and PE concentration were predictive of shorter MPM patient survival (13.0 vs 8.3 months, p < 0.0001, in PE). Finally, BDNF did not affect MPM cell oncogenic properties but was implicated in PE-induced angiogenesis. In conclusion, BDNF appears to be a new interesting biomarker for MPM and could also be a new therapeutic target regarding its implication in angiogenesis.

Erector Spinae Plane Block versus Paravertebral Block after Thoracic Surgery for Lung Cancer: A Propensity Score Study.

INTRODUCTION: The prevention of respiratory complications is a major issue after thoracic surgery for lung cancer, and requires adequate post-operative pain management. The erector spinae plane block (ESPB) may decrease post-operative pain. The objective of this study was to evaluate the impact of ESPB on pain after video or robot-assisted thoracic surgery (VATS or RATS). METHODS: The main outcome of this retrospective study with a propensity score analysis (PSA) was to compare the post-operative pain at 24 h at rest and at cough between a group that received ESPB and a group that received paravertebral block (PVB). Post-operative morphine consumption at 24 h and complications were also assessed. RESULTS: One hundred and seven patients were included: 54 in the ESPB group and 53 in the PVB group. The post-operative median pain score at rest and cough was lower in the ESPB group compared to the PVB group at 24 h (respectively, at rest 2 [1; 3.5] vs. 2 [0; 4], p = 0.0181, with PSA; ESPB -0.80 [-1.50; -0.10], p = 0.0255, and at cough (4 [3; 6] vs. 5 [4; 6], p = 0.0261, with PSA; ESPB -1.48 [-2.65; -0.31], p = 0.0135). There were no differences between groups concerning post-operative morphine consumption at 24 h and respiratory complications. CONCLUSIONS: Our results suggest that ESPB is associated with less post-operative pain at 24 h than PVB after VATS or RATS for lung cancer. Furthermore, ESPB is an acceptable and safe alternative compared to PVB.

Comparison of lobectomy performed through Toumai® surgical robot and da Vinci surgical robot in early-stage non-small cell lung cancer: a retrospective study of early perioperative results.

Background: Robotic-assisted thoracic surgery (RATS) is a safe and efficient minimally invasive thoracic approach compared to thoracotomy. Today, almost all thoracic procedures can be performed by RATS. In recent years, the Chinese government has issued some policies to support the development of domestic surgical robots, leading to the development of the Toumai® surgical robot system. This study aimed to explore the application of the Toumai® surgical robot in performing lobectomy for early-stage non-small cell lung cancer (NSCLC), and to compare its safety, surgical effect, and advantages or disadvantages compared with the mature da Vinci robotic surgical system. Methods: Patients with early-stage NSCLC undergoing robotic-assisted lobectomy in our center between November 2021 and December 2021 were enrolled in the study; Surgeries were performed through the Toumai® surgical robot and the da Vinci robotic system. Anatomical lobectomy and systematic lymph node (LN) dissection were conducted in all patients. Baseline and perioperative outcomes were analyzed to compare the two methods. Results: The combined 19 patients from the Toumai® group (n=9) and the da Vinci group (n=10) were enrolled and eligible for analyses. They had similar baseline characteristics, tumor characteristics, clinical stage, and pathological stage. Conversion to thoracotomy was not observed, and the operation time {95 minutes [interquartile range (IQR), 86.5-136.5 minutes] vs. 86 minutes (IQR, 81-102 minutes), P=0.178} and other perioperative outcomes were comparable in the two groups. There was no significant difference in the number of dissected LNs and lymphatic stations between both groups. Conclusions: The application of Toumai® surgical robot in lobectomy was preliminarily shown to be safe and effective. Compared with the mature da Vinci robotic surgery system, Toumai® surgical robot had similar technical and surgical advantages, highlighting its suitability as an optional method for the new generation of robotic-assisted thoracoscopic surgery.

Midterm survival of imaging-assisted robotic lung segmentectomy for non-small-cell lung cancer.

OBJECTIVES: Our goal was to report our midterm results using imaging-assisted modalities with robotic segmentectomies for non-small-cell lung cancer (NSCLC). METHODS: This was a retrospective study of all robotic segmentectomies, with confirmed NSCLC, performed at our general and thoracic surgery unit in the Rouen University Hospital (France), from January 2012 through December 2019. Benign and metastatic lesions were excluded. Data were extracted from the EPITHOR French nationwide database. RESULTS: A total of 121 robotic segmentectomies were performed for 118 patients with a median age of 65 (interquartile range: 60, 69) years. The majority had clinical stage T1aN0M0 (71.9%) or T1bN0M0 (13.2%). The mean (standard deviation) number of resected segments was 1.93 (1.09) with 80.2% imaging-assisted segmentectomies. Oriented (according to tumour location) or systematic lymphadenectomy or sampling was performed for 72.7%, 23.1% and 4.1% of patients. The postoperative course was uneventful for 94 patients (77.7%), whereas 34 complications occurred for 27 patients (22.3%), including 2 patients (1.7%) with Clavien-Dindo ≥III complications. The mean thoracic drainage duration was 4.12 days, and the median hospital stay was 4 days (interquartile range: 3, 5) after the operation. The 2-year survival rate was 93.9% (95% confidence interval: 86.4-97.8%). Excluding stage IV (n = 3) and stage 0 tumours (n = 6), the 2-year survival rate was 95.7% (95% confidence interval: 88.4-98.8%) compared to an expected survival rate of 94.0% according to stage-specific survival rates found in a large external reference cohort. CONCLUSIONS: Imaging-guided robotic-assisted thoracic surgery segmentectomy seems to be useful and oncological with good midterm results, especially for patients with early-stage NSCLC.

Long-Term Survival Following Minimally Invasive Lung Cancer Surgery: Comparing Robotic-Assisted and Video-Assisted Surgery.

BACKGROUND: Nowadays, video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS) are known to be safe and efficient surgical procedures to treat early-stage non-small cell lung cancer (NSCLC). We assessed whether RATS increased disease-free survival (DFS) compared with VATS for lobectomy and segmentectomy. METHODS: This retrospective cohort study included patients treated for resectable NSCLC performed by RATS or VATS, in our tertiary care center from 2012 to 2019. Patients' data were prospectively recorded and reviewed in the French EPITHOR database. Primary outcomes were 5-year DFS for lobectomy and 3-year DFS for segmentectomy, compared by propensity-score adjusted difference of Kaplan-Meier estimates. RESULTS: Among 844 lung resections, 436 VATS and 234 RATS lobectomies and 46 VATS and 128 RATS segmentectomies were performed. For lobectomy, the adjusted 5-year DFS was 60.9% (95% confidence interval (CI) 52.9-68.8%) for VATS and 52.7% (95%CI 41.7-63.7%) for RATS, with a difference estimated at -8.3% (-22.2-+4.9%, p = 0.24). For segmentectomy, the adjusted 3-year DFS was 84.6% (95%CI 69.8-99.0%) for VATS and 72.9% (95%CI 50.6-92.4%) for RATS, with a difference estimated at -11.7% (-38.7-+7.8%, p = 0.21). CONCLUSIONS: RATS failed to show its superiority over VATS for resectable NSCLC.

The 6-minute stepper test and the sit-to-stand test predict complications after major pulmonary resection via minimally invasive surgery: a prospective inception cohort study.

QUESTIONS: How well do the 6-minute stepper test (6MST) and sit-to-stand test (STST) predict complications after minimally invasive lung cancer resection? Do the 6MST and STST provide supplementary information on the risk of postoperative complications in addition to the prognostic variables that are currently used, such as age and the American Society of Anesthesiology (ASA) score? DESIGN: Prospective inception cohort study with follow-up for 90 days. PARTICIPANTS: Consecutive sample of adults undergoing major lung resection with video-assisted thoracic surgery (VATS) or robot-assisted thoracic surgery (RATS). OUTCOME MEASURES: Patients had a preoperative functional evaluation with the 6MST and STST. The number of steps, heart rate change, saturation and dyspnoea during the 6MST and the number of lifts during the STST were recorded. Complications graded ≥ 2 on the Clavien-Dindo classification were recorded for 90 days after surgery. RESULTS: Between November 2018 and November 2019, 118 patients with a mean age of 65 years (SD 9) were included and analysed. Their surgeries were via VATS in 88 (75%) and via RATS in 30 (25%). For predicting a postoperative complication graded ≥ 2 on the Clavien-Dindo classification, the area under the Receiver Operating Characteristic curve was: 0.82 (95% CI 0.75 to 0.90) for the number of steps during the 6MST, with an optimum cut-off of 140 steps; and 0.85 (95% CI 0.77 to 0.93) for the number of lifts during the STST, with an optimum cut-off of 20 lifts. CONCLUSION: The 6MST and STST predicted morbidity and mortality after lung cancer resection via minimally invasive surgery. The preoperative use of these exercise tests in clinical practice may be useful for risk stratification. REGISTRATION: NCT03824977.

The Role of Surgery in Lung Cancer Treatment: Present Indications and Future Perspectives-State of the Art.

Non-small cell lung cancers (NSCLC) are different today, due to the increased use of screening programs and of innovative systemic therapies, leading to the diagnosis of earlier and pre-invasive tumors, and of more advanced and controlled metastatic tumors. Surgery for NSCLC remains the cornerstone treatment when it can be performed. The role of surgery and surgeons has also evolved because surgeons not only perform the initial curative lung cancer resection but they also accompany and follow-up patients from pre-operative rehabilitation, to treatment for recurrences. Surgery is personalized, according to cancer characteristics, including cancer extensions, from pre-invasive and local tumors to locally advanced, metastatic disease, or residual disease after medical treatment, anticipating recurrences, and patients' characteristics. Surgical management is constantly evolving to offer the best oncologic resection adapted to each NSCLC stage. Today, NSCLC can be considered as a chronic disease and surgery is a valuable tool for the diagnosis and treatment of recurrences, and in palliative conditions to relieve dyspnea and improve patients' comfort.

Surgery for lung cancer: postoperative changes and complications-what the Radiologist needs to know.

Imaging findings after thoracic surgery can be misleading. Knowledge of the normal post-operative anatomy helps the radiologist to recognise life-threatening complications and conversely not to wrongly evoke a complication in cases of trivial post-operative abnormalities. In this educational article, we reviewed the expected patterns after thoracic surgery including sublobar resection, lobectomy, pneumonectomy and related techniques. Imaging aspects of frequent and less common complications and their typical imaging features are then presented.

Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. METHODS: Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. RESULTS: Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. CONCLUSIONS: This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.

Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival.

Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo-molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well annotated with histologic, molecular and clinical data of patients. Targeted next-generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioid-like and sarcomatoid-like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2, and LATS2 were more frequent in nonepithelioid MPM and positively associated with the S.score. BAP1, NF2, TERT promoter, TP53, and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2, and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival.

Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications.

Malignant pleural mesothelioma (MPM) is recognized as heterogeneous based both on histology and molecular profiling. Histology addresses inter-tumor and intra-tumor heterogeneity in MPM and describes three major types: epithelioid, sarcomatoid and biphasic, a combination of the former two types. Molecular profiling studies have not addressed intra-tumor heterogeneity in MPM to date. Here, we use a deconvolution approach and show that molecular gradients shed new light on the intra-tumor heterogeneity of MPM, leading to a reconsideration of MPM molecular classifications. We show that each tumor can be decomposed as a combination of epithelioid-like and sarcomatoid-like components whose proportions are highly associated with the prognosis. Moreover, we show that this more subtle way of characterizing MPM heterogeneity provides a better understanding of the underlying oncogenic pathways and the related epigenetic regulation and immune and stromal contexts. We discuss the implications of these findings for guiding therapeutic strategies, particularly immunotherapies and targeted therapies.

[Molecular heterogeneity of malignant pleural mesotheliomas]. / Hétérogénéité moléculaire des mésothéliomes pleuraux malins.

Malignant pleural mesothelioma (MPM) is predominantly an occupational cancer, most often linked to asbestos exposure. Malignant pleural mesothelioma prognosis is poor with a short survival median, due to the aggressiveness of tumor cells and the weak efficiency of conventional anti-cancer therapies. Clinical, histological, and molecular data suggest tumor heterogeneity between patients as it was also shown for other cancer types. Consequently, there is an urgent need to develop new therapies that take into account this heterogeneity and the molecular characteristics of malignant pleural mesothelioma, in particular by identifying new anti-cancer drugs targeting the molecular specificities of each malignant pleural mesothelioma. Malignant pleural mesothelioma is characterized by numerous molecular alterations at the chromosomal, genetic and epigenetic levels. Molecular classification based on gene expression profile has firstly defined two tumor groups, C1 and C2, and more recently, four groups. By integrating genetic and transcriptomic analysis, a C2LN tumor subgroup of the C2 group has been identified and characterized. In addition to tumor heterogeneity between patients, intra-tumor heterogeneity is supported by several evidences. Most therapeutic strategies that take into account the tumor molecular characteristics have focused on targeted therapies based on mutated genes. A more appropriate strategy would be to consider better-defined tumor groups on the basis of several molecular alterations types as it has been proposed for the C2LN subgroup. A robust definition of homogeneous tumor groups sharing common molecular characteristics is necessary for the development of effective precision medicine for malignant pleural mesothelioma.

Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma.

OBJECTIVES: Malignant pleural mesothelioma (MPM) is an aggressive tumor with limited therapeutic options, requiring the development of efficient targeted therapies based on molecular phenotype of the tumor and to identify predictive biomarkers of the response. MATERIALS AND METHODS: The effect of inhibitors was investigated by cell viability assessment on primary MPM cell lines established in our laboratory from patient tumors, well characterized at the molecular level. Effects on apoptosis, cell proliferation and viability on MPM growing in multicellular spheroid were also assessed for verteporfin. Gene and protein expression, and gene knockdown by RNA interference were used to define mechanism of inhibition and specific predictive biomarkers. RESULTS: Anti-tumor effect of eight major signaling pathways inhibitors involved in mesothelial carcinogenesis was investigated. Three inhibitors were more efficient than cisplatin, the drug used as first-line chemotherapy in patients with MPM: verteporfin, a putative YAP inhibitor, defactinib, a FAK inhibitor and NSC668394, an Ezrin inhibitor. Verteporfin, the most efficient inhibitor, induced cell proliferation arrest and cell death, and is effective on 3D spheroid multicellular model. Verteporfin sensitivity was YAP-independent and related to molecular classification of the tumors. Biomarkers based on gene expression were identified to predict accurately sensitivity to these three inhibitors. CONCLUSION: Our study shows that drug screening on well-characterized MPM cells allows for the identification of novel potential therapeutic strategies and defining specific biomarkers predictive of the drug response.