SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma.

BACKGROUND: The combination of pemetrexed and cisplatin remains the reference first-line systemic therapy for malignant pleural mesothelioma (MPM). Its activity is moderate because of tumor aggressiveness, immune-suppressive environment and resistance to chemotherapy-induced immunogenic cell death (ICD). Preliminary and limited findings suggest that MPM cells have deregulated ubiquitination and proteasome activities, although proteasome inhibitors achieved disappointing clinical results. METHODS: Here, we investigated the role of the E3-ubiquitin ligase SKP/Cullin/F-box (SCF) complex in cell cycle progression, endoplasmic reticulum (ER)/proteostatic stress and ICD in MPM, and the therapeutic potential of the neddylation/SCF complex inhibitor MLN4924/Pevonedistat. RESULTS: In patient-derived MPM cultures and syngenic murine models, MLN4924 and cisplatin showed anti-tumor effects, regardless of MPM histotype and BAP1 mutational status, increasing DNA damage, inducing S- and G2/M-cell cycle arrest, and apoptosis. Mechanistically, by interfering with the neddylation of cullin-1 and ubiquitin-conjugating enzyme UBE2M, MLN4924 blocks the SCF complex activity and triggers an ER stress-dependent ICD, which activated anti-MPM CD8+T-lymphocytes. The SKP2 component of SCF complex was identified as the main driver of sensitivity to MLN4924 and resistance to cisplatin. These findings were confirmed in a retrospective MPM patient series, where SKP2 high levels were associated with a worse response to platinum-based therapy and inferior survival. CONCLUSIONS: We suggest that the combination of neddylation inhibitors and cisplatin could be worth of further investigation in the clinical setting for MPM unresponsive to cisplatin. We also propose SKP2 as a new stratification marker to determine the sensitivity to cisplatin and drugs interfering with ubiquitination/proteasome systems in MPM.

Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer generally diagnosed at an advanced stage and characterized by a poor prognosis. The absence of alterations in druggable kinases, together with an immune-suppressive tumor microenvironment, limits the use of molecular targeted therapies, making the treatment of MPM particularly challenging. Here we investigated the in vitro susceptibility of MPM to lurbinectedin (PM01183), a marine-derived drug that recently received accelerated approval by the FDA for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. METHODS: A panel of primary MPM cultures, resembling the three major MPM histological subtypes (epithelioid, sarcomatoid, and biphasic), was characterized in terms of BAP1 status and histological markers. Subsequently, we explored the effects of lurbinectedin at nanomolar concentration on cell cycle, cell viability, DNA damage, genotoxic stress response, and proliferation. RESULTS: Stabilized MPM cultures exhibited high sensitivity to lurbinectedin independently from the BAP1 mutational status and histological classification. Specifically, we observed that lurbinectedin rapidly promoted a cell cycle arrest in the S-phase and the activation of the DNA damage response, two conditions that invariably resulted in an irreversible DNA fragmentation, together with strong apoptotic cell death. Moreover, the analysis of long-term treatment indicated that lurbinectedin severely impacts MPM transforming abilities in vitro. CONCLUSION: Overall, our data provide evidence that lurbinectedin exerts a potent antitumoral activity on primary MPM cells, independently from both the histological subtype and BAP1 alteration, suggesting its potential activity in the treatment of MPM patients.

Which Is the Best Treatment in Recurrent Thymoma? A Systematic Review and Meta-Analysis.

BACKGROUND: Optimal recurrent thymoma management remains arguable because of limited patient numbers, and relatively late and variable recurrence patterns. Given the absence of high-quality evidence and relatively small study cohorts, we performed a quantitative meta-analysis to determine the outcome of surgical and non-surgical approaches assessing the five-year overall survival (5y overall survival (OS)) in patients with recurrent thymoma. METHODS: We performed a comprehensive literature search and analysis according to PRISMA guidelines of studies published from 1 January 1980 until 18 June 2020 from PubMed/MEDLINE, EMBASE, and Scopus. We included studies with the cohorts' superior to 30 patients describing recurrent thymoma treatment, comparing surgical and non-surgical approaches reporting survival data. RESULTS: Literature search revealed 3017 articles. Nine studies met all inclusion criteria and were selected for the meta-analysis. The recurrences were local/regional in 73-98% of cases and multiple in 49-72%. After treatment, 5y OS ranged from 48-77% and 10y OS from 37-51%. The quantitative meta-analysis showed a better outcome comparing surgical vs other treatments. Two studies showed statistically significant risk differences in the 5y OS favoring complete resection. After pooling results of seven studies using the random model, the combined 5y OS risk difference was 0.39, with lower and upper limits of 0.16 and 0.62, respectively (p = 0.001), and a moderate heterogeneity among studies (p = 0.098, I2 = 43.9%). Definitive conclusions could not be drawn regarding the prognostic impact of myasthenia gravis, histology, and patterns of relapse reported in literature. CONCLUSIONS: Surgical treatment after thymoma recurrence is associated with a significant better 5y OS; therefore, surgical resection should be preferred in all technically feasible cases.

Report of an interactive three-dimensional anatomical model to be used as an intraoperative aid in lung anatomical resections for non-small lung cancer.

The possibility of using three-dimensional reconstructions as an intraoperative aid to thoracic surgeons has not yet been fully explored. With this in mind, we developed a technology based on a three-dimensional virtual model of lungs obtained from lung computed tomography scans, the Hyper-Accuracy Three-Dimensional reconstruction (HA3D™), which aids the surgeon during surgery. We tested this technology while performing a uniportal video-assisted thoracic surgery right upper lobectomy for lung cancer.

Results of Surgical Resection of Locally Advanced Pulmonary Neuroendocrine Tumors.

BACKGROUND: Pulmonary neuroendocrine tumors include well-differentiated and poorly differentiated histology for which cell type has proved to be a determinant of survival in many studies. In patients diagnosed with bronchial carcinoid and large cell neuroendocrine carcinoma (LCNEC), surgery is the treatment of choice even in the case of locally advanced disease with lymph node involvement. METHODS: We retrospectively analyzed patients undergoing anatomic lung resection for bronchial carcinoid or LCNEC with lymph node involvement (N1/N2) at the final pathologic examination (pN+). Characteristics of patients and differences in overall survival and disease-free survival are presented according to tumor type. Overall survival of distinct histologic groups was compared with survival in our institutional experience in stage I patients, without nodal involvement (pN0). RESULTS: In all, 325 patients underwent surgical resection for neuroendocrine tumors; 89 patients had nodal involvement. Five-year survival was 89% in pN+ bronchial carcinoid both for typical carcinoid and atypical carcinoid but worse for pN+ LCNEC (47%). Cell type did not influence the prognosis in N0 disease, and no differences in survival were evident between N0 and N+ in the bronchial carcinoid group. In the group of LCNEC, 5-year overall survival was much worse for pN+ LCNEC (47%) compared with pN0 LCNEC (91%). CONCLUSIONS: Bronchial carcinoids have the best prognosis, and surgery remains the treatment of choice for both early and locally advanced disease. On the contrary, aggressive forms (LCNEC) with lymph nodal metastasis have a poor prognosis, and they need to be treated with an aggressive multidisciplinary approach.

Anterior chest wall resection and sternal body wedge for primary chest wall tumour: reconstruction technique with biological meshes and titanium plates.

Chest wall tumours are heterogeneous neoplasms, either primary or metastatic, with a malignancy rate of 50%. Surgical resection is one of the mainstays of the treatment, however, chest wall resections can be particularly challenging depending onto the resection size, site and patient habitus. The surgical strategy should be carefully analysed preoperatively, keeping in mind the need of an oncological radical resection (R0) in accordance to the reconstruction principles elicited by le Roux and Sherma since 1983, which include restoring the chest wall rigidity, preserving pulmonary mechanics, protect the intrathoracic organs, avoiding paradox movements of the chest cavity and, possibly, to reduce the thoracic deformity. In this context, we herewith report our surgical reconstruction technique following an anterior chest wall resection and sternal body wedge for a primary chest wall tumour (chondrosarcoma).

Surgical management of chronic diaphragmatic hernias.

Chronic diaphragmatic hernia (CDH) is an uncommon disease which may be associated with significant morbidity and mortality. Antecedent (even many months or years before CDH development) blunt or penetrating thoracic/thoraco-abdominal trauma is generally recognized. A wide spectrum of different mechanisms of injury, timing in presentation, size of the diaphragmatic defect, types and amount of abdominal viscera herniated into the chest cavity, clinical symptoms are observed in CDHs. Thoracic and abdominal CT scan (with coronal, axial and sagittal reconstructions) is the best diagnostic tool; sometimes thoracic MRI is needed to better define the extent of the diaphragmatic defect and the number of abdominal organs displaced into the chest cavity. Surgery (sometimes urgent) represents the treatment of choice for CDH; diaphragmatic hernia direct repair with a tension-free suture is generally attempted; in case of very large defects or when a tension-free suture is deemed unfeasible, the use of prosthesis is recommended. This review article will discuss about CDH aetiology, clinical presentation diagnosis and surgical treatment.

Pneumonectomy in Stage IIIA-N2 NSCLC: Should It Be Considered After Neoadjuvant Chemotherapy?

BACKGROUND: Owing to the expected poor long-term outcomes and high postoperative morbidity and mortality, patients with stage IIIA-N2 tumors candidate to pneumonectomy (PN) are usually excluded from surgery. This study aims to analyze the outcome of patients who underwent PN to prove its safety and feasibility. PATIENTS AND METHODS: We retrospectively analyzed data from 233 patients who underwent PN for N2 non-small-cell lung cancer (NSCLC) between 1998 and 2015. Eighty-five patients were occult N2 disease (group 1), whereas 148 patients underwent induction therapy (IT) for stage IIIA-N2 (group 2). RESULTS: Overall morbidity, postoperative mortality, and 90-day mortality rates were 46.8%, 2.6%, and 8.6%, respectively. The 2 groups (group 1 vs. 2) had similar postoperative and 90-day mortality rates: 2.4% versus 2.7% (P = 1.00), and 9.4% versus 8.1% (P = .81), respectively. The incidence of major morbidity was higher and statistically significant in group 2 compared with group 1: 23% versus 12.9% (P = .1). Postoperative bronchopleural fistula occurred in 4.7% (4/85) of patients with occult N2 (group 1) and in 10.1% (15/148) of patients undergoing IT (group 2) (P = .10). Median overall survival (OS) was 2.2 years, with a 3 and 5-year OS of 43.4% and 31.6%, respectively. Disease-free survival (DFS) was 1.5 years, with 3 and 5-year DFS of 41.6% and 32%, respectively; no difference in OS and DFS between the 2 groups was found. CONCLUSIONS: Considering the acceptable morbidity and mortality rate and the long-term survival, PN should not be excluded for selected patients with stage IIIA-N2 NSCLC as a matter of principle.

Diagnostic and Therapeutic Implications of Pulmonary Lymphoma Associated With Nodular Amyloidosis.

Pulmonary localization of B-cell lymphoma associated with deposits of amyloid material is a rare finding in the thoracic disease spectrum. This report describes a rare case of nodular pulmonary amyloidosis in a 50-year-old patient. He underwent left upper lobectomy for mucosa-associated lymphoid tissue lymphoma that originated from bronchial lymphoid tissue.

Emergency drain for post pneumonectomy bronchopleural fistula: a drain placement technique based on the siphon principle.

Post pneumonectomy bronchopleural fistula (BPF) is a life-threatening complication requiring pleural cavity drainage to avoid acute mediastinal shift and contralateral aspiration pneumonia. Chest drain insertion in this situation may be technically difficult because of drastic anatomical changes such as mediastinal dislocation, diaphragm elevation and, sometimes, massive subcutaneous emphysema. In addition, the most important part of the pleural cavity to be drained is the costophrenic recess that is scarcely drained by a standard chest tube with its tip aiming high and upwards. We propose a safe, simple and effective technique based on the siphon principle to drain the lowest part of the pleural cavity.

Training in Uniportal Video-Assisted Thoracic Surgery.

Interest in uniportal video-assisted thoracic surgery (VATS) is rapidly growing worldwide because it represents the surgical approach to the lung with the least possible trauma. Specific training in this surgical approach is crucial due to its technical implications, to perform it safely while upholding the required therapeutic radicality. Novel strategies, such as interactive learning technologies, simulators, high-volume preceptorships, and targeted proctorships, play important roles in the training for uniportal VATS which, ideally, should be standardized, governed, and credentialed by national and international surgical societies to ensure patient safety and academic responsibility.

Coronary artery disease is associated with an increased mortality rate following video-assisted thoracoscopic lobectomy.

OBJECTIVE: To compare the incidence of major adverse cardiac events (MACE) and mortality following video-assisted thoracoscopic surgery (VATS) lobectomy in patients with and without coronary artery disease (CAD). METHODS: Multicentre retrospective analysis of 1699 patients undergoing VATS lobectomy (January 2012-March 2015). CAD definition: previous acute myocardial infarct (AMI), angina, percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). MACE definition: postoperative acute myocardial ischemia, cardiac arrest or any cardiac death. Propensity score analysis was performed to match patients with and without CAD. Outcomes of the 2 matched groups were compared. RESULTS: The incidence of MACE and mortality for the entire population was 0.4% (7 patients) and 1.7% (29 patients); 218 patients (13%) had a history of CAD: 106 previous AMI, 55 angina, 32 CABG, and 81 PCI. The propensity score yielded 2 well-balanced groups of 218 pairs with and without CAD. MACE (CAD 2 [0.9%] vs no-CAD 1 [0.5%]; P = 1), cardiovascular and pulmonary complications (CAD 61 [28%] vs no-CAD 51 [23%]; P = .3) and postoperative stay (CAD 7.3 days vs no-CAD 6.2 days; P = .3) were not different between the groups. The incidence of atrial fibrillation (CAD 31 [14%] vs no-CAD 18 [8.2%]; P = .07), 30-day mortality (CAD: 11 [5%] vs no-CAD 2 [0.9%]; P = .02) and death among complicated patients (CAD 18% vs no-CAD 3.9%; P = .009) were higher in the CAD group. CONCLUSIONS: The incidence of MACE following VATS lobectomy in patients with CAD is low and similar to patients without CAD. However, their risk of postoperative mortality is fivefold higher compared with non-CAD patients, warranting refined preoperative functional evaluation and more intense postoperative monitoring.

Management of Chest Drains After Thoracic Resections.

Immediately after lung resection, air tends to collect in the retrosternal part of the chest wall (in supine position), and fluids in its lower part (costodiaphragmatic sinus). Several general thoracic surgery textbooks currently recommend the placement of 2 chest tubes after major pulmonary resections, one anteriorly, to remove air, and another into the posterior and basilar region, to drain fluids. Recently, several authors advocated the placement of a single chest tube. In terms of air and fluid drainage, this technique demonstrated to be as effective as the conventional one after wedge resection or uncomplicated lobectomy.

Errors and Complications in Chest Tube Placement.

Chest drain placement is one of the most common surgical procedures performed in routine clinical practice. Despite the many benefits, chest tube insertion is not always a harmless procedure, and potential significant morbidity and mortality may exist. The aim of this article was to highlight the correct chest tube placement procedure and to focus on errors and clinical complications following its incorrect insertion into the chest.

Primary lung tumors invading the chest wall.

Chest wall (CW) involvement occurs in approximately 5% of all primary lung neoplasms. According to the most recent TNM classification, lung tumors invading CW are classified as T3, and they represent approximately 45% of all T3 lung cancers. The most common clinical symptom at presentation is chest pain (>60%), which is highly specific of CW infiltration (>90%). Dyspnoea and hemoptysis are also described, especially in case of large lesions. A realistic chance to cure locally advanced tumors invading CW is a surgical resection, consisting in the excision of the primary lung cancer along with the involved CW (sometimes an "en-bloc" resection) and an appropriate lymph-nodal dissection. However, such patients are at high-risk of facing postoperative complications; prognosis mainly depends on: (I) the completeness of resection; and (II) the lymph-nodal involvement. Hence, due to these reasons (incidence, symptoms, prognosis, post-operative complications), such category of patients are to be carefully assessed preoperatively and if deemed practicable, surgery should be taken into consideration. In this view, the aim of this paper is to critically review the most recent series of lung tumors invading the CW, with a particular focus on patients' preoperative evaluation, surgical techniques, postoperative complications and overall outcome.

Validation of EORTC and CALGB prognostic models in surgical patients submitted to diagnostic, palliative or curative surgery for malignant pleural mesothelioma.

BACKGROUND: To assess the trend of our surgical patients affected by malignant pleural mesothelioma (MPM) and submitted to diagnostic/palliative or curative surgical procedures and to validate the European Organisation for Research and Treatment of Cancer (EORTC) prognostic score in our patient population. METHODS: This is a cohort study of patients submitted to surgery for MPM from January 2007 to December 2013. Primary outcome was overall survival (OS). Univariate and multivariate-adjusted comparisons by EORTC prognostic score for OS were accomplished using Cox method. Adjusted models included the following clinical variables: kind of procedure, smoking habit, asbestos exposure, Charlson's Comorbidity Index (CCI), clinical tumor stage, adjuvant chemotherapy, dyspnoea, chest pain and haematological variables according to the score features. Nomenclature of the surgical procedures matches the International Association for the Study Lung Cancer (IASLC)/International Mesothelioma Interest Group (iMIG). RESULTS: One-hundred sixty-six consecutive cases were collected: the median age at surgery was 73 years and 123 patients (75%) had a history of asbestos exposure. Ninty patients (54%) were submitted to a palliative/diagnostic thoracoscopy, 30 to pleurectomy/decortication (P/D), and 6 to extra-pleural pneumonectomy (EPP). Clinical TNM stages were as follows: 99 (60%) stage I-II, 34 (20%) stage III and 33 (20%) stage IV. The median follow-up (FU) was 19 months [interquartile range (IQR), 9-31 months] and the FU-completeness was 98%. By the end of the study 130 patients died (78%). One- and 3-year OS was 60% and 36%, respectively. Patients submitted to EPP and P/D showed a better survival (P=0.013). Multivariable model showed an independent prognostic value of EORTC score (HR =2.86, P<0.001). CONCLUSIONS: In selected patients, aggressive surgical approaches, although not radical, may still be beneficial. The EORTC prognostic index proved to be an independent prognostic factor in our cohort of patients and therefore is a reliable and valid instrument that may be implemented in the daily practice.

When size matters: changing opinion in the management of pleural space-the rise of small-bore pleural catheters.

Tube thoracostomy is usually the first step to treat several thoracic/pleural conditions such as pneumothorax, pleural effusions, haemothorax, haemo-pneumothorax and empyema. Today, a wide range of drains is available, ranging from small to large bore ones. Indications for an appropriate selection remains yet matter of debate, especially regarding the use of small bore catheters. Through this paper, we aimed to retrace the improvements of drains through the years and to review the current clinical indications for chest drain placement in pleural/thoracic diseases, comparing the effectiveness of small-bore drains vs. large-bore ones.

VATS lobectomy program: the trainee perspective.

Due to its intrinsic characteristics, video assisted thoracic surgery (VATS) lobectomy is currently the recommended surgical approach for early stage lung cancer treatment. The importance of increasing the number of surgeons capable of performing VATS lobectomies is implicit and of utmost importance. In fact, the need of performing independently and routinely VATS lobectomies for early stage lung cancer will soon be a prerequisite to the new generation of thoracic surgeons. The feeling that VATS lobectomy teaching should be part of their training is strongly felt among trainees but, at the moment, a formal, uniform and certified process of learning VATS lobectomy is not available in all training centres. Perhaps, through the supervision, support and aid from national and European Thoracic Surgery Societies, programs of integration of recognized, standardized and certified teaching of VATS lobectomy could be planned and undertaken by the training centres, both at national as well as European level.