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Abstract Background In patients with resectable stage III non-small cell lung cancer (NSCLC), induction chemoimmunotherapy followed by surgical resection has shown unprecedented rates of pathological response and event-free survival. However, a triple-induction including radiochemotherapy and immunotherapy followed by surgical resection has not been routinely established in clinical practice. Case presentation We report the case of a 47-year-old patient with stage IIIA NSCLC who was treated in a combined concept including induction concurrent radiochemotherapy, followed by 4 cycles of pembrolizumab and subsequent intrapericardial left-sided pneumonectomy. Histological analysis revealed a pathological complete response. Conclusions The case demonstrates that the combination of neoadjuvant chemo-, radio- and immunotherapy in advanced NSCLC may lead to a relevant down-staging and may enable a R0-resection of a borderline resectable tumor. However, the combination of four different treatment modalities requires resilience and a good performance status. A triple induction treatment may be a promising option for selected patients with locally advanced NSCLC and good performance status.

With the emergence of lung cancer screening programmes and newly detected localised and multifocal disease, novel treatment compounds and multimodal treatment approaches, the treatment landscape of non-small cell lung cancer is becoming increasingly complex. In parallel, in-depth molecular analyses and clonality studies are revealing more information about tumorigenesis, potential therapeutical targets and the origin of lesions. All can play an important role in cases with multifocal disease, oligoprogression and oligorecurrence. In multifocal disease, it is essential to understand the relatedness of separate lesions for treatment decisions, because this information distinguishes separate early-stage tumours from locally advanced or metastatic cancer. Clonality studies suggest that a majority of same-histology lesions represent multiple primary tumours. With the current standard of systemic treatment, oligoprogression after an initial treatment response is a common scenario. In this state of induced oligoprogressive disease, local ablative therapy by either surgery or radiotherapy is becoming increasingly important. Another scenario involves the emergence of a limited number of metastases after radical treatment of the primary tumour, referred to as oligorecurrence, for which the use of local ablative therapy holds promise in improving survival. Our review addresses these complex situations in lung cancer by discussing current evidence, knowledge gaps and treatment recommendations.

Objective: Pleural adhesions (PLAs) have been shown to be a possible risk factor for air leak after lung volume reduction surgery (LVRS), but the relevance of PLA for lung function outcome remains unclear. We analyzed our LVRS cohort for the influence of PLA on short-term (ie, prolonged air leak) and long-term outcomes. Methods: Retrospective observational cohort study with 187 consecutive patients who underwent LVRS from January 2016 to December 2019. PLA were defined as relevant if they were distributed extensively at the dorsal pleura; were present in at least at 2 areas, including the dorsal pleura; or present extensively at the mediastinal pleura. In patients with bilateral emphysema, bilateral LVRS was performed preferentially. The objectives were to quantify the association of PLA and rate of prolonged air leak (chest tube >7 days), and the association of PLA with postoperative exacerbations and with forced expiratory volume in 1 second 3 months postoperatively. The associations were quantified with odds ratios for binary outcomes, and with between-group differences for continuous outcomes. To account for missing observations, 100-fold multiple imputation was used. Results: PLAs were found in 46 of 187 patients (24.6%). There was a 32.6% rate of prolonged air leak (n = 61), mean chest tube time was 7.84 days. A total of 94 (50.3%) LVRSs were unilateral and 93 were bilateral. There was evidence for an association between PLA and the rate of prolonged air leak (odds ratio, 2.83; 95% CI, 1.36 to 5.89; P = .006). There was no evidence for an association between PLA and postoperative exacerbations (odds ratio, 1.11; 95% CI, 0.5 to 2.45; P = .79). There was no evidence for an association between PLA and forced expiratory volume in 1 second (estimate −1.52; 95% CI –5.67 to 2.63; P = .47). Both unilateral and bilateral LVRS showed significant postoperative improvements in forced expiratory volume in 1 second by 27% (8.43 units; 95% CI, 3.66-13.12; P = .0006) and by 28% (7.87 units; 95% CI, 4.68-11.06; P

Abstract Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients showing good initial response to immune checkpoint inhibitors, followed by acquired resistance at later time points. By using imaging mass cytometry and whole exome and RNA sequencing, we detect two patterns of resistance¨: One group of patients is characterized by reduced numbers of tumor-infiltrating CD8+ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group shows high CD8+ T cell infiltration and high expression of PD-L1 in addition to markedly elevated expression of other immune-inhibitory molecules. In two cases, we detect downregulation of type I and II IFN pathways following progression to resistance, which could lead to an impaired anti-tumor immune response. This study thus captures the development of immune checkpoint inhibitor resistance as it progresses and deepens our mechanistic understanding of immunotherapy response in NSCLC.

Background and purpose: To analyze clinical trial activities and patient recruitment numbers into prospective clinical studies for solid malignancies during the COVID-19 pandemic in a tertiary cancer center. Materials and methods: Patient recruitment numbers in prospective clinical studies of solid malignancies were retrospectively analyzed for the years 2019 – 2021 at the Comprehensive Cancer Center Zurich (CCCZ). Changes in recruitment numbers were tested for association with organ-specific subunits, as well as organizational and treatment-related trial characteristics. To assess differences between categorical variables, Chi-squared test was used. For uni- and multivariate analysis, Cox proportional hazards were calculated. Results: In 2019, there were a total of 107 studies (registry trials, clinical phase I-III trials, and translational studies) recruiting 304 patients at the CCCZ. During the COVID-19 pandemic in 2020 and 2021, there were 120 and 125 active trials with a total recruitment of 355 and 666 patients, respectively. No significant differences between the subunits and study characteristics in changes of patient recruitment in clinical phase I-III trials were identified when the year prior to the COVID-19 pandemic (2019) was compared to the first year of the pandemic (2020) and to 2020-2021. Conclusions: Despite healthcare systems around the world have experienced significant disruption due to the COVID-19 pandemic, data from our tertiary cancer center showed that clinical trial activities were maintained at a high level during the pandemic.

Selection of patients who may benefit from extracorporeal life support (ECLS) as a bridge to lung transplant (LTx) is crucial. The aim was to assess if validated prognostic scores could help in selecting patients who may benefit from ECLS-bridging predicting their outcomes. Clinical data of patients successfully ECLS-bridged to LTx from 2009 to 2021 were collected from two European centers. For each patient, we calculated Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score III (SAPS III), Acute Physiology and Chronic Health Evaluation II (APACHE II), before placing ECLS support, and then correlated with outcome. Median values of SOFA, SAPS III, and APACHE II were 5 (IQR 3–9), 57 (IQR 47.5–65), and 21 (IQR 15–26). In-hospital, 30 and 90 days mortality were 21%, 14%, and 22%. SOFA, SAPS III, and APACHE II were analyzed as predictors of in-hospital, 30 and 90 days mortality (SOFA C-Index: 0.67, 0.78, 0.72; SAPS III C-index: 0.48, 0.45, 0.51; APACHE II C-Index: 0.49, 0.45, 0.52). For SOFA, the score with the best performance, a value ≥9 was identified to be the optimal cut-off for the prediction of the outcomes of interest. SOFA may be considered an adequate predictor in these patients, helping clinical decision-making. More specific and simplified scores for this population are necessary.

We previously observed increased levels of adenosine‐deaminase‐acting‐on‐dsRNA (Adar)‐dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR‐dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR‐mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1‐associated protein 1 wild‐type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type‐1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures.

Abstract Background An inadequate donor left atrial cuff is a rare technical issue after graft procurement for lung transplantation. With regard to the shortage of suitable donor organs for lung transplantation, these organs should be surgically reconstructed to avoid the loss of an organ and a futile intervention in the critically ill recipient. Case presentation We report a case of a 62-year old patient who underwent bilateral sequential lung transplantation for chronic obstructive pulmonary disease. During isolated lung procurement, the right inferior pulmonary vein was circumferentially transsected and separated from the right superior pulmonary and middle lobe veins. Subsequently, a reconstruction of the left atrial cuff with an acellular biological patch was performed to complete the atrium anastomosis. The patient experienced an uneventful postoperative recovery and a follow-up ventilation/perfusion scan showed normal perfusion of the right lower lobe. Conclusions This case demonstrates that reconstruction of an inadequate left atrial cuff with a biological patch is feasible and allows for an adequate venous drainage and therefore normal transplant organ function.

Background: Primary chest wall sarcomas are a rare and heterogeneous group of chest wall tumors that require multimodal oncologic and surgical therapy. The aim of this study was to review our experience regarding the surgical treatment of chest wall sarcomas, evaluating the short- and long-term results. Methods: In this retrospective single-center study, patients who underwent surgery for soft tissue and bone sarcoma of the chest wall between 1999 and 2018 were included. We analyzed the oncologic and surgical outcomes of chest wall resections and reconstructions, assessing overall and recurrence-free survival and the associated clinical factors. Results: In total, 44 patients underwent chest wall resection for primary chest wall sarcoma, of which 18 (41%) received surgery only, 10 (23%) received additional chemoradiotherapy, 7% (3) received surgery with chemotherapy, and 30% (13) received radiotherapy in addition to surgery. No perioperative mortality occurred. Five-year overall survival was 51.5% (CI 95%: 36.1–73.4%), and median overall survival was 1973 days (CI 95% 1461; -). As determined in the univariate analysis, the presence of metastasis upon admission and tumor grade were significantly associated with shorter survival (p = 0.037 and p < 0.01, respectively). Five-year recurrence-free survival was 71.5% (95% CI 57.6%; 88.7%). Tumor resection margins and metastatic disease upon diagnosis were significantly associated with recurrence-free survival (p < 0.01 and p < 0.01, respectively). Conclusion: Surgical therapy is the cornerstone of the treatment of chest wall sarcomas and can be performed safely. Metastasis and high tumor grade have a negative influence on overall survival, while tumor margins and metastasis have a negative influence on local recurrence.

Background: Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (CTEPH) with accessible lesions. Breathing pure oxygen (hyperoxia) during right heart catheterization (RHC) allows for the calculation of the right-to-left shunt fraction (Qs/Qt). In the absence of intracardiac shunt, Qs/Qt can be used as a marker of ventilation–perfusion mismatch in patients with CTEPH. This study involved investigating Qs/Qt after PEA and its relation to other disease-specific outcomes. Study design and Methods: This study is a retrospective study that focuses on patients with operable CTEPH who had Qs/Qt assessment during RHC before and 1 year after PEA. Additionally, 6 min walking distance (6MWD), WHO functional class (WHO-FC), and NT-proBNP were assessed to calculate a four-strata risk score. Results: Overall, 16 patients (6 females) with a median age of 66 years (quartiles 55; 74) were included. After PEA, an improvement in mean pulmonary artery pressure (38 [32; 41] to 24 [18; 28] mmHg), pulmonary vascular resistance (5.7 [4.0; 6.8] to 2.5 [1.4; 3.8] WU), oxygen saturation (92 [88; 93]% to 94 [93; 95]%), WHO-FC, and risk score was observed (all p < 0.05). No improvement in median Qs/Qt could be detected (13.7 [10.0; 17.5]% to 13.0 [11.2; 15.6]%, p = 0.679). A total of 7 patients with improved Qs/Qt had a significant reduction in risk score compared to those without improved Qs/Qt. Conclusion: PEA did not alter Qs/Qt assessed after 1 year in operable CTEPH despite an improvement in hemodynamics and risk score, potentially indicating a persistent microvasculopathy. In patients whose shunt fraction improved with PEA, the reduced shunt was associated with an improvement in risk score.

CDKN2A deletion is a common alteration in pleural mesothelioma (PM) and frequently associated with co-deletion of MTAP. Since the standard detection method for CDKN2A deletion and FISH analysis is relatively expensive, we here investigated the suitability of inexpensive p16 and MTAP IHC by comparing concordance between IHC and OncoScan CNV arrays on samples from 52 PM patients. Concordance was determined using Cohen’s kappa statistics. Loss of CDKN2A was associated with co-deletion of MTAP in 71% of cases. CDKN2A-MTAP copy-number normal cases were also IHC positive in 93% of cases for p16 and 100% for MTAP, while homozygous deletion of CDKN2A-MTAP was always associated with negative IHC for both proteins. In cases with heterozygous CDKN2A-MTAP loss, IHC expression of p16 and MTAP was negative in 100% and 71%, respectively. MTAP and p16 IHC showed high sensitivity (MTAP 86.5%, p16 100%) and specificity (MTAP 100%, p16 93.3%) for the detection of any gene loss. Loss of MTAP expression occurred exclusively in conjunction with loss of p16 labeling. Both p16 and MTAP IHC showed high concordance with Oncoscan CNV arrays (kappa = 0.952, p < 0.0001, and kappa = 0.787, p < 0.0001 respectively). We recommend combined MTAP and p16 immunohistochemistry to confirm the diagnosis of PM.

This pilot study conducted in Switzerland aims to assess the implementation, execution, and performance of low-dose CT lung cancer screening (LDCT-LCS). With lung cancer being the leading cause of cancer-related deaths in Switzerland, the study seeks to explore the potential impact of screening on reducing mortality rates. However, initiating a lung cancer screening program poses challenges and depends on country-specific factors. This prospective study, initiated in October 2018, enrolled participants meeting the National Lung Cancer Study criteria or a lung cancer risk above 1.5% according to the PLCOm2012 lung cancer risk-model. LDCT scans were assessed using Lung-RADS. Enrollment and follow-up are ongoing. To date, we included 112 participants, with a median age of 62 years (IQR 57–67); 42% were female. The median number of packs smoked each year was 45 (IQR 38–57), and 24% had stopped smoking before enrollment. The mean PLCOm2012 was 3.7% (±2.5%). We diagnosed lung cancer in 3.6% of participants (95%, CI:1.0–12.1%), with various stages, all treated with curative intent. The recall rate for intermediate results (Lung-RADS 3,4a) was 15%. LDCT-LCS in Switzerland, using modified inclusion criteria, is feasible. Further analysis will inform the potential implementation of a comprehensive lung cancer screening program in Switzerland.

We previously demonstrated that cullin 4B (CUL4B) upregulation was associated with worse outcomes of pleural mesothelioma (PM) patients, while the overexpression of its paralog CUL4A was not associated with clinical outcomes. Here, we aimed to identify the distinct roles of CUL4B and CUL4A in PM using an siRNA approach in PM cell lines (ACC Meso-1 and Mero82) and primary culture. The knockdown of CUL4B and CUL4A resulted in significantly reduced colony formation, increased cell death, and delayed cell proliferation. Furthermore, similar to the effect of CUL4A knockdown, downregulation of CUL4B led to reduced expression of Hippo pathway genes including YAP1, CTGF, and survivin. Interestingly, CUL4B and not CUL4A knockdown reduced TGF-β1 and MMP2 expression, suggesting a unique association of CUL4B with this pathway. However, the treatment of PM cells with exogenous TGF-β1 following CUL4B knockdown did not rescue PM cell growth. We further analyzed ACC Meso-1 xenograft tumor tissues treated with the cullin inhibitor, pevonedistat, which targets protein neddylation, and observed the downregulation of human TGF-β1 and MMP2. In summary, our data suggest that CUL4B overexpression is important for tumor cell growth and survival and may drive PM aggressiveness via the regulation of TGF-β1 expression and, furthermore, reveal a new mechanism of action of pevonedistat.

Abstract Objectives Tumor thickness and tumor volume measured by computed tomography (CT) were suggested as valuable prognosticator for patients’ survival diagnosed with malignant pleural mesothelioma (MPM). The purpose was to assess the accuracy of CT scan based preoperatively measured tumor volume and thickness compared to actual tumor weight of resected MPM specimen and pathologically assessed tumor thickness, as well as an analysis of their impact on overall survival (OS). Methods Between 09/2013–08/2018, 74 patients were treated with induction chemotherapy followed by (extended) pleurectomy/decortication ((E)PD). In 53 patients, correlations were made between CT-measured volume and -tumor thickness (cTV and cTT) and actual tumor weight (pTW) based on the available values. Further cTV and pT/IMIG stage were correlated using Pearson correlation. Overall survival (OS) was calculated with Kaplan Meier analysis and tested with log rank test. For correlation with OS Kaplan-Meier curves were made and log rank test was performed for all measurements dichotomized at the median. Results Median pathological tumor volume (pTV) and pTW were 530 ml [130 ml – 1000 ml] and 485 mg [95 g – 982 g] respectively. Median (IQR) cTV was 77.2 ml (35.0–238.0), median cTT was 9.0 mm (6.2–13.7). Significant association was found between cTV and pTV (R = 0.47, p

Cell lines are extensively used to study cancer biology. However, the use of highly passaged commercial cell lines has to be questioned, as they do not closely resemble the originating tumor. To understand the reliability of preclinical models for Malignant pleural mesothelioma (MPM) studies, we have performed whole transcriptome and whole exome analyses of fresh frozen MPM tumors and compared them to cell lines generated from these tumors, as well as commercial cell lines and a preclinical MPM mouse model. Patient-derived cell lines were generated from digested fresh tumors and whole exome sequencing was performed on DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor samples, corresponding patient-derived cell lines, and normal tissue. RNA sequencing libraries were prepared from 10 fresh frozen tumor samples, the 10 corresponding patient-derived cell lines, and 7 commercial cell lines. Our results identified alterations in tumor suppressor genes such as FBXW7, CDKN2A, CDKN2B, and MTAP, all known to drive MPM tumorigenesis. Patient-derived cell lines correlate to a high degree with their originating tumor. Gene expressions involved in multiple pathways such as EMT, apoptosis, myogenesis, and angiogenesis are upregulated in tumor samples when compared to patient-derived cell lines; however, they are downregulated in commercial cell lines compared to patient-derived cell lines, indicating significant differences between the two model systems. Our results show that the genome and transcriptome of tumors correlate to a higher degree with patient-derived cell lines rather than commercial cell lines. These results are of major relevance for the scientific community in regard to using cell lines as an appropriate model, resembling the pathway of interest to avoid misleading results for clinical applications.

The coronavirus disease 2019 (COVID-19) pandemic has had a severe impact on oncological and thoracic surgical practice worldwide. In many hospitals, the care of COVID-19 patients required a reduction of elective surgery, to avoid viral transmission within the hospital, and to save and preserve personnel and material resources. Cancer patients are more susceptible to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and are at an increased risk of a severe course of disease. In many patients with lung cancer, this risk is further increased owing to comorbidities, older age and a pre-existing lung disease. Surgical resection is an important part of the treatment in patients with early stage or locally advanced non-small cell lung cancer, but the treatment of these patients during the COVID-19 pandemic becomes a challenging balance between the risk of patient exposure to SARS-CoV-2 and the need to provide timely and adequate cancer treatment despite limited hospital capacities. This manuscript aims to provide an overview of the surgical treatment of lung cancer patients during the COVID-19 pandemic including the triage and prioritisation as well as the surgical approach, and our own experience with cancer surgery during the first pandemic wave. We furthermore aim to highlight the risk and potential consequences of delayed lung cancer treatment due to the deferral of surgery, screening appointments and follow-up visits. With much attention being diverted to COVID-19, it is important to retain awareness of cancer patients, maintain oncological surgery and avoid treatment delay during the pandemic.

Abstract Pulmonary hypertension (PH), especially pulmonary arterial and chronic thromboembolic pulmonary hypertension (PAH/CTEPH), are rare and progressive conditions. Despite recent advances in treatment and prognosis, PH is still associated with impaired quality of life and survival. Long‐term PH‐registry data provide information on the changing PH‐epidemiology and may help to direct resources to patient's needs. This retrospective analysis of the Swiss Pulmonary Hypertension Registry includes patients newly diagnosed with PH (mainly PAH/CTEPH) registered from January 2001 to June 2019 at 13 Swiss hospitals. Patient characteristics (age, body mass index, gender, diagnosis), hemodynamics at baseline, treatment, days of follow‐up, and events (death, transplantation, pulmonary endarterectomy, or loss to follow‐up) at last visit were analyzed. Patients were stratified into four time periods according to their date of diagnosis. Survival was analyzed overall and separately for PAH/CTEPH and time periods. 1427 PH patients were included (thereof 560 PAH, 383 CTEPH). Over the years, age at baseline (mean ± SD) significantly increased from 59 ± 14 years in 2001–2005 to 66 ± 14 years in 2016–2019 (p

Background: Extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) is highly abandoned due to high morbidity and mortality rates and impaired quality of life (QoL). However, there are still rare indications for this intervention. The aim of this longitudinal prospective study was to monitor QoL and lung function in patients undergoing EPP and compare the outcomes with extended pleurectomy/decortication [(E)PD].Methods: Between June 2013 and June 2017, 42 patients underwent induction chemotherapy followed by either EPP (n = 7) or (E)PD (n = 35). All patients filled out the EORTC QLC-C15-PAL, –LC13, and SF-36 self-rating questionnaires pre-operatively, 6 weeks and 4 months after the operation. Additionally, lung function was measured pre-operatively and 4 months post-operatively.Results: We observed no significant differences in all QoL categories (general global health, pain, and dyspnea) between both surgical procedures, over the whole observation period. Moreover, a general tendency toward restoration of the pre-operative QoL status was documented at 4 months after the both operations. Forced expiratory volume in 1 s (FEV1) showed a significant decrease after surgery in both the groups [EPP group p = 0.06 and (E)PD group p < 0.001]; also, the forced volume vital capacity (FVC) significantly decreased (EPP group p = 0.046 P/D group

Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct form of precapillary pulmonary hypertension classified as group 4 by the World Symposium on Pulmonary Hypertension (WSPH) and should be excluded during an episode of acute pulmonary embolism (PE). Patients presenting to emergency departments with sudden onset of signs and symptoms of acute PE may already have a pre-existing CTEPH condition decompensated by the new PE episode. Identifying an underlying and undiagnosed CTEPH during acute PE, while challenging, is an important consideration as it will alter the patients’ acute and long-term management. Differential diagnosis and evaluation require an interdisciplinary expert team. Analysis of the clinical condition, the CT angiogram, and the hemodynamic situation are important considerations; patients with CTEPH usually have significantly higher sPAP at the time of index PE, which is unusual and unattainable in the context of acute PE and a naïve right ventricle. The imaging may reveal signs of chronic disease such as right ventricle hypertrophy bronchial collaterals and atypical morphology of the thrombus. There is no standard for the management of acute on chronic CTEPH. Herein, we provide a diagnostic and management algorithm informed by several case descriptions and a review of the literature.

Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

Ischemia-reperfusion injury compromises short- and long-term outcomes after lung transplantation. The scarce existing data on NAD+ suggest effects on hypoxia-induced vasoconstriction, on reactive oxygen species and on tampering inflammation. We exposed rat lungs to 14 h of cold ischemic storage and perfused them in a rat ex vivo lung perfusion (EVLP) system for 4 h. A control group (n = 6) was compared to groups receiving 100 µM (n = 6) or 200 µM NAD+ (n = 6) in the preservation solution and groups receiving 200 µM (n = 4) or 2000 µM (n = 6) NAD+ every 30 min in the perfusate, starting at 1 h of EVLP. Compared to the control, significant effects were only achieved in the 2000 µM NAD+ group. During the 4 h of EVLP, we monitored higher vascular flow, lower mean pulmonary arterial pressure and increased oxygenation capacity. Tissue inflammation estimated with the myeloperoxidase assay was lower in the 2000 µM NAD+ group. We observed higher levels of anti-inflammatory IL-10, higher anti-inflammatory IL-6/IL-10 ratios and lower levels of pro-inflammatory IL-12 and IL-18 as well as a trend of more anti-inflammatory IFNy in the 2000 µM NAD+ perfusate. In the bronchoalveolar lavage, the pro-inflammatory levels of IL-1α and IL-1β were lower in the 2000 µM NAD+ group. NAD+ administered during EVLP is a promising agent with both anti-inflammatory properties and the ability to improve ischemic lung function.

BACKGROUND We aimed to analyse the nodal spread of our non-small cell lung cancer pN2 cohort according to tumour location, the possible implications of an unusual spreading pattern, and other factors influencing postoperative survival after anatomical lung resection. METHODS In this retrospective observational study, clinical data was collected for 124 consecutive non-small cell lung cancer (NSCLC) patients with a pathological N2 (stage IIIA or B) undergoing anatomical lung resection at our institution between 2001 and 2010. Cox regression was used to analyse independent predictors of 5-year overall survival and recurrence-free survival. RESULTS A total of 105 patients were included in the final analysis. Tumour location in the right upper lobe and middle lobe was significantly more often associated with involvement of lymph node stations 2 and 4 than NSCLC in the right lower lobe (station 2: right upper vs right lower lobe, p = 0.001 and middle vs right lower lobe, p = 0.038; station 4: right upper vs right lower lobe, p

Use of normothermic ex vivo lung perfusion (EVLP) was adopted in clinical practice to assess the quality of marginal donor lungs. Subnormothermic perfusion temperatures are in use among other solid organs to improve biochemical, clinical and immunological parameters. In a rat EVLP model of donation after circulatory death (DCD) lung donors, we tested the effect of four subnormothermic EVLP temperatures that could further improve organ preservation. Warm ischemic time was of 2 hours. EVLP time was of 4 hours. Lung physiological data were recorded and metabolic parameters were assessed. Lung oxygenation at 21°C and 24°C were significantly improved whereas pulmonary vascular resistance and edema formation at 21°C EVLP were significantly worsened when compared to 37°C EVLP. The perfusate concentrations of potassium ions and lactate exiting the lungs with 28°C EVLP were significantly lower whereas sodium and chlorine ions with 32°C EVLP were significantly higher when compared to 37°C EVLP. Also compared to 37°C EVLP, the pro-inflammatory chemokines MIP2, MIP-1α, GRO-α, the cytokine IL-6 were significantly lower with 21°C, 24°C and 28°C EVLP, the IL-18 was significantly lower but only with 21°C EVLP and IL-1β was significantly lower at 21°C and 24°C EVLP. Compared to the 37°C EVLP, the lung tissue ATP content after 21°C, 24°C and 28°C EVLP were significantly higher, the carbonylated protein content after 28°C EVLP was significantly lower and we measured significantly higher myeloperoxidase activities in lung tissues with 21°C, 24°C and 32°C. The 28°C EVLP demonstrated acceptable physiological variables, significantly higher lung tissue ATP content and decreased tissue carbonylated proteins with reduced release of pro-inflammatory cytokines. In conclusion, the 28°C EVLP is a non inferior setting in comparison to the clinically approved 37°C EVLP and significantly improve biochemical, clinical and immunological parameters and may reduce I/R injuries of DCD lung donors.

ObjectivesTo evaluate CT-derived radiomics for machine learning-based classification of thymic epithelial tumor (TET) stage (TNM classification), histology (WHO classification) and the presence of myasthenia gravis (MG).MethodsPatients with histologically confirmed TET in the years 2000-2018 were retrospectively included, excluding patients with incompatible imaging or other tumors. CT scans were reformatted uniformly, gray values were normalized and discretized. Tumors were segmented manually; 15 scans were re-segmented after 2 weeks by two readers. 1316 radiomic features were calculated (pyRadiomics). Features with low intra-/inter-reader agreement (ICCResults105 patients undergoing surgery for TET were identified. After applying exclusion criteria, 62 patients (28 female; mean age, 57±14 years; range, 22-82 years) with 34 low-risk TET (LRT; WHO types A/AB/B1), 28 high-risk TET (HRT; WHO B2/B3/C) in early stage (49, TNM stage I-II) or advanced stage (13, TNM III-IV) were included. 14(23%) of the patients had MG. 334(25%) features were excluded after intra-/inter-reader analysis. Discriminatory performance of the random forest classifiers was good for histology(AUC, 87.6%; 95% confidence interval, 76.3-94.3) and TNM stage(AUC, 83.8%; 95%CI, 66.9-93.4) but poor for the prediction of MG (AUC, 63.9%; 95%CI, 44.8-79.5).ConclusionsCT-derived radiomic features may be a useful imaging biomarker for TET histology and TNM stage.

ObjectivesAdding bevacizumab, an anti-Vascular Endothelial Growth Factor (VEGF), to platinum-based chemotherapy/pemetrexed in 1st line treatment of advanced malignant pleural mesothelioma (MPM), significantly improved overall survival. However, increased high grade bleeding after operation was reported in patients with colorectal cancer who previously received bevacizumab. In the present analysis, we assessed for the first time the impact of adding bevacizumab to induction chemotherapy prior to surgery for mesothelioma patients.MethodsTwo hundred twenty-seven MPM patients, intended to be treated with induction chemotherapy followed by surgery at the University Hospital of Zurich between 2002 and December 2018, were included in the present analysis. After propensity score matching for gender, histology and age (1:3 ratio), data from 88 patients were analyzed. Sixty-six patients underwent induction chemotherapy (with cis-/carboplatin and pemetrexed: control group) alone and 22 patients underwent induction chemotherapy with the addition of bevacizumab (bevacizumab group) prior macroscopic complete resection (MCR). Perioperative and long-term outcome variables were analyzed.ResultsPatients undergoing combination treatment with bevacizumab had a significantly better response than with chemotherapy alone as assessed by modified RECIST (p=0.046). Intraoperative complications in the bevacizumab group (one patient), or in the control group (three patients) were not related to intraoperative bleeding. Postoperative transfusion of blood products occurred in a larger amount in the control group than in the bevacizumab group (p=0.047). Overall survival was not statistically different between both groups.ConclusionThese initial data demonstrate that MCR can be performed safely after triple induction chemotherapy with bevacizumab without increased intra- and postoperative bleeding complications. Response rates were significantly improved by the addition of bevacizumab.

We assessed the value of dual-energy CT pulmonary angiography (CTPA) for classification of the level of disease in chronic thromboembolic pulmonary hypertension (CTEPH) patients compared to the surgical Jamieson classification and prediction of hemodynamic changes after pulmonary endarterectomy. Forty-three CTEPH patients (mean age, 57 ± 16 years; 18 females) undergoing CTPA prior to surgery were retrospectively included. “Proximal” and “distal disease” were defined as L1 and 2a (main and lobar pulmonary artery [PA]) and L2b-4 (lower lobe basal trunk to subsegmental PA), respectively. Three radiologists had a moderate interobserver agreement for the radiological classification of disease (k = 0.55). Sensitivity was 92–100% and specificity was 24–53% to predict proximal disease according to the Jamieson classification. A median of 9 segments/patient had CTPA perfusion defects (range, 2–18 segments). L1 disease had a greater decrease in the mean pulmonary artery pressure (p = 0.029) and pulmonary vascular resistance (p = 0.011) after surgery compared to patients with L2a to L3 disease. The extent of perfusion defects was not associated with the level of disease or hemodynamic changes after surgery (p > 0.05 for all). CTPA is highly sensitive for predicting the level of disease in CTEPH patients with a moderate interobserver agreement. The radiological level of disease is associated with hemodynamic improvement after surgery.

Background: We evaluated the prognostic value of Sarcopenia, low precardial adipose-tissue (PAT), and high tumor-volume in the outcome of surgically-treated pleural mesothelioma (PM). Methods: From 2005 to 2020, consecutive surgically-treated PM-patients having a pre-operative computed tomography (CT) scan were retrospectively included. Sarcopenia was assessed by CT-based parameters measured at the level of the fifth thoracic vertebra (TH5) by excluding fatty-infiltration based on CT-attenuation. The findings were stratified for gender, and a threshold of the 33rd percentile was set to define sarcopenia. Additionally, tumor volume as well as PAT were measured. The findings were correlated with progression-free survival and long-term mortality. Results: Two-hundred-seventy-eight PM-patients (252 male; 70.2 ± 9 years) were included. The mean progression-free survival was 18.6 ± 12.2 months, and the mean survival time was 23.3 ± 24 months. Progression was associated with chronic obstructive pulmonary disease (COPD) (p = p = 0.001), and type of surgery (p = 0.026). Three-year mortality was associated with higher patient age (p = 0.005), presence of COPD (p < 0.001), higher tumor-stage (p = 0.015), and higher tumor-volume (p < 0.001). Kaplan-Meier statistics showed that sarcopenic patients have a higher three-year mortality (p = 0.002). While there was a negative correlation of progression-free survival and mortality with tumor volume (r = 0.281, p = 0.001 and r = −0.240, p < 0.001; respectively), a correlation with PAT could only be shown for epithelioid PM (p = 0.040). Conclusions: Sarcopenia as well as tumor volume are associated with long-term mortality in surgically treated PM-patients. Further, while there was a negative correlation of progression-free survival and mortality with tumor volume, a correlation with PAT could only be shown for epithelioid PM.

Background The key issues for performing lung volume reduction surgery (LVRS) is the identification of the target zones. Recently introduced three-dimensional computed tomography rendering methods are used to identify the morphological distribution and its severity of lung emphysema by densitometry. We demonstrate a new software for emphysema imaging and show the pre- and post-operative results in patients undergoing LVRS planned based on this new technology. Methods A real-time three-dimensional image analysis software system was used pre- and 3 months post-operatively in five patients with heterogeneous emphysema and a single patient with homogeneous morphology scheduled for LVRS. Focus was on low attenuation areas with

One-fourth of all patients with metastatic non-small cell lung cancer presents with a limited number of metastases and relatively low systemic tumor burden. This oligometastatic state with limited systemic tumor burden may be associated with remarkably improved overall and progression-free survival if both primary tumor and metastases are treated radically combined with systemic therapy. This local aggressive therapy (LAT) requires a multidisciplinary approach including medical oncologists, radiation therapists, and thoracic surgeons. A surgical resection of the often advanced primary tumor should be part of the radical treatment whenever feasible. However, patient selection, timing, and a correct treatment allocation for LAT appear to be essential. In this review, we aimed to summarize and discuss the current evidence on patient selection criteria such as characteristics of the primary tumor and metastases, response to neoadjuvant or first-line treatment, molecular characteristics, mediastinal lymph node involvement, and other factors for LAT in oligometastatic NSCLC.

Ex vivo lung perfusion (EVLP) has been implemented to increase the number of donor lungs available for transplantation. The use of K(ATP) channel modulators during EVLP experiments may protect against lung ischemia-reperfusion injury and may inhibit the formation of reactive oxygen species. In a rat model of donation after circulatory death with 2 h warm ischemic time, we evaluated rat lungs for a 4-hour time in EVLP containing either mitochondrial-specific or plasma membrane and/or sarcolemmal-specific forms of K(ATP) channel modulators. Lung physiological data were recorded, and metabolic parameters were assessed. When compared to the control group, in the EVLP performed with diazoxide or 5-hydroxydecanoic acid (5-HD) we recorded significantly lower pulmonary vascular resistance and only in the diazoxide group recorded significant lung weight loss. In the perfusate of the 5-HD group, interleukin-1β and interleukin-1α were significantly lower when compared to the control group. Perfusate levels of calcium ions were significantly higher in both 5-HD and cromakalim groups, whereas the levels of calcium, potassium, chlorine and lactate were reduced in the diazoxide group, although not significantly when compared to the control. The use of a diazoxide mitochondrial-specific K(ATP) channel opener during EVLP improved lung physiological and metabolic parameters and reduced edema.

Despite many developments in recent years, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. Therefore, additional research, aiming to further elucidate the underlying molecular mechanisms of malignant transformation and development of therapy resistance, as well as the identification of additional novel therapeutic avenues, is crucial. For this purpose, reliable in vitro models are indispensable, as they allow for quick identification of suspected oncogenic drivers or evaluation of novel therapeutic strategies in a timely and cost-effective fashion. However, standard two-dimensional cell culture systems, the most frequently used in vitro model, are usually not truly representative of the situation in a patient as these models lack the tumor heterogeneity, the surrounding tumor microenvironment and the three-dimensional complexity of a tumor in vitro. For this reason, 3D cell culture systems, in particular organoids generated from normal non-malignant cells or tumor cell-based organoids (tumoroids), have in recent years gained much attention as alternative in vitro model systems that more closely resemble the actual primary tumor. In this review, we provide an overview of the available literature in the field of NSCLC organoids, which might still be in its infancy, but is gaining momentum.

The quality of marginal donor lungs is clinically assessed with normothermic machine perfusion. Although subnormothermic temperature and perfluorocarbon-based oxygen carriers (PFCOC) have proven favourable for other organ transplants, their beneficial use for ex vivo lung perfusion (EVLP) still requires further investigation. In a rat model, we evaluated on a 4 h EVLP time the effects of PFCOC with either 28 °C or 37 °C perfusion temperatures. During EVLP at 28 °C with PFCOC, we recorded significantly lower lung pulmonary vascular resistance (PVR), higher dynamic compliance (Cdyn), significantly lower potassium and lactate levels, higher lung tissue ATP content, and significantly lower myeloperoxidase tissue activity when compared to the 37 °C EVLP with PFCOC. In the subnormothermic EVLP with or without PFCOC, the pro-inflammatory mediator TNFα, the cytokines IL-6 and IL-7, the chemokines MIP-3α, MIP-1α, MCP-1, GRO/KC as well as GM-CSF, G-CSF and the anti-inflammatory cytokines IL-4 and IL-10 were significantly lower. The 28 °C EVLP improved both Cdyn and PVR and decreased pro-inflammatory cytokines and pCO2 levels compared to the 37 °C EVLP. In addition, the 28 °C EVLP with PFCOC produced a significantly lower level of myeloperoxidase activity in lung tissue. Subnormothermic EVLP with PFCOC significantly improves lung donor physiology and ameliorates lung tissue biochemical and inflammatory parameters.

Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment.

Introduction: Therapy options for patients with oligoprogressive malignant pleural mesothelioma (MPM) are limited. Stereotactic Body Radiotherapy (SBRT) may be a promising therapeutic option, as it delivers a localized ablative dose of radiation and therefore balances efficacy and treatment related toxicities. The intent of this retrospective analysis was to evaluate the feasibility of SBRT for limited pleural recurrences.Methods and Materials: This retrospective single-institution study is based on the 21 consecutive patients treated with hypofractionated radiotherapy for oligoprogressive MPM. Clinical and radiological data was collected at regular follow-up visits including toxicity, local control and survival.Results: At primary diagnosis, 57% of the patients presented with stage III disease. Initial treatment of MPM consisted of induction chemotherapy (n = 12) prior to a macroscopic complete resection (n = 18). Three patients received additional intracavitary chemotherapy and another three patients were treated with chemotherapy alone without another treatment at the time of first diagnosis. A total of 50 lesions in recurrent MPM were treated with SBRT. The median number of radiotherapy fractions was 5 (range 3–20) with a median dose per fraction of 5 Gy (range 2.5–12.5 Gy). The median total treatment dose was 30 Gy (20–50 Gy) with a median prescription isodose line (IDL) of 65% (65–100%). Median follow-up of all patients from diagnosis was 28 months (range 7–152 months). Analyzing all lesions separately, the 12-months-local control from SBRT was 73.5%. The median progression free survival (PFS) after SBRT was 6 months (range 0–21 months) and the median OS from first first SBRT was 29 months (range 0–61 months). Only one patients experienced above Grade 3 toxicities.Conclusion: This analysis demonstrates the feasibility of a SBRT approach for oligorecurrent MPM. SBRT was well-tolerated even after multiple repetitions and local control was high with a promising median OS.

AIM OF THE STUDY Non-intubated, video-assisted thoracoscopic surgery (NiVATS) has been successfully developed in several centres worldwide. Local anaesthesia techniques and techniques to perform thoracoscopic surgery on a spontaneously breathing lung are the two key elements which must be adopted to establish a NiVATS programme. We established NiVATS by performing bilateral, uniportal sympathectomies, and compared it to classical video-assisted thoracoscopic surgery (VATS) under general anaesthesia with double-lumen intubation. METHODS Ten consecutive bilateral VATS sympathectomies were compared with ten consecutive NiVATS procedures. Nineteen of the procedures were for palmar hyperhidrosis and one was for facial blushing. Duration of anaesthesia, surgery and hospitalisation, perioperative complications, side effects and quality of life before and after sympathectomy were analysed. RESULTS Median age was 26.5 years (range 17–55) and mean BMI in the NiVATS group was 21.8 (range 19.1–26.3). NiVATS sympathectomies were performed as outpatient procedures significantly more often (9/10 vs 3/10, p = 0.008). Quality of life was significantly increased after sympathectomy in all patients, with no significant differences between the NiVATS and the VATS groups. There were no differences between the two groups regarding compensatory sweating (40 vs 50%, p = 0.66). The duration of anaesthesia, not including the time required for the surgery, was significantly shorter in the NiVATS group (p

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro, however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially fatal disease, which may occur as a rare complication after acute pulmonary embolism, although the exact epidemiology of CTEPH is unknown. The mechanisms involved in nonresolution of thrombotic material and scarring of large and/or small pulmonary arteries are unknown; some risk factors have been identified. To date, CTEPH is still underdiagnosed and undertreated. The cardinal symptom of CTEPH is dyspnoea on exertion, but diagnosis is challenging owing to nonspecific symptoms. Right heart catheterisation is mandatory for the diagnosis of pulmonary hypertension, followed by several imaging methods including besides ventilation/perfusion scan, computed tomography pulmonary angiography and conventional angiography. Operability assessment by a multidisciplinary team is crucial for the management in all CTEPH patients, as pulmonary endarterectomy (PEA) remains the only curative treatment of choice. PEA leads to substantial improvement of haemodynamics, symptoms, and life expectancy enabling many patients to lead unrestricted lives under sole anticoagulation therapy. For inoperable patients or those with disease not amenable to surgery, medical therapy or balloon angioplasty are emerging treatment options. Owing to the complexity of CTEPH, the diagnosis and treatment of CTEPH patients is reserved exclusively to experienced CTEPH centres.

Normothermic machine perfusion is clinically used to assess the quality of marginal donor lungs. Although subnormothermic temperatures have proven beneficial for other solid organ transplants, subnormothermia-related benefits of ex vivo lung perfusion (EVLP) still need to be investigated. Material and Methods: In a rat model, we evaluated the effects of 28 °C temperature on 4-h EVLPs with subsequent left lung transplantation. The recipients were observed for 2 h postoperatively. Lung physiology data were recorded and metabolic parameters were assessed. Results: During the 4-h subnormothermic EVLP, the lung oxygenation was significantly higher (p < 0.001), pulmonary vascular resistance (PVR) lower and dynamic compliance (Cdyn) higher when compared to the 37 °C EVLP. During an end-of-EVLP stress test, we recorded significantly higher flow (p < 0.05), lower PVR (p < 0.05) and higher Cdyn (p < 0.01) in the 28 °C group when compared to the 37 °C group. After the left lung transplantation, Cdyn and oxygenation improved in the 28 °C group, which were comparable to the 37 °C group. Chemokines RANTES, MIP-3α, MIP-1α MCP-1 GRO/KC and pro-inflammatory mediators GM-CSF, G-CSF and TNFα were significantly lower after the 28 °C EVLP and remained low in the plasma of the recipient rats after transplantation. The lungs of the 28 °C group showed significantly lowered myeloperoxidase activity and lowered levels of TNFα and IL-1β. Conclusions: Compared to the normothermic perfusion, the 28 °C EVLP improved Cdyn and PVR and reduced both the release of pro-inflammatory cytokines and myeloperoxidase activity in lung tissue. These observations were also observed after the left lung transplantation in the subnormothermic group. The 28 °C EVLP significantly improved biochemical, physiological and inflammatory parameters in lung donors.

Neurofibromatosis type 2 (NF2), the tumor suppressor frequently lost in malignant pleural mesothelioma (MPM), suppresses tumorigenesis in part by inhibiting the Cullin4 ubiquitin ligase (CUL4) complex in the nucleus. Here, we evaluated the importance of CUL4 in MPM progression and tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation. CUL4 paralogs (CUL4A and CUL4B) were upregulated in MPM tumor specimens compared to nonmalignant pleural tissues. High gene and protein expressions of CUL4B was associated with a worse progression-free survival of MPM patients. Among 13 MPM cell lines tested, five (38%) were highly sensitive to pevonedistat (half maximal inhibitory concentration of cell survival IC50 < 0.5 µM). This remained true in a 3D spheroid culture. Pevonedistat treatment caused the accumulation of CDT1 and p21 in both sensitive and resistant cell lines. However, the treatment induced S/G2 cell cycle arrest and DNA rereplication predominantly in the sensitive cell lines. In an in vivo mouse model, the pevonedistat treatment significantly prolonged the survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth in sensitive tumors but increased apoptosis in resistant tumors. The mechanism in the resistant tumor model may be mediated by reduced macrophage infiltration, resulting from the suppression of macrophage chemotactic cytokines, C-C motif chemokine ligand 2 (CCL2), expression in tumor cells.

Background: Ex vivo lung perfusion (EVLP) is a technology that allows the re-evaluation of questionable donor lung before implantation and it has the potential to repair injured donor lungs that are otherwise unsuitable for transplantation. We hypothesized that perfluorocarbon-based oxygen carrier, a novel reconditioning strategy instilled during EVLP would improve graft function. Methods: We utilized perfluorocarbon-based oxygen carrier (PFCOC) during EVLP to recondition and improve lung graft function in a pig model of EVLP and lung transplantation. Lungs were retrieved and stored for 24 h at 4 °C. EVLP was done for 6 h with or without PFCOC. In the transplantation groups, left lung transplantation was done after EVLP with or without PFCOC. Allograft function was assessed by means of pulmonary gas exchange, lung mechanics and vascular pressures, histology and transmission electron microscopy (TEM). Results: In the EVLP only groups, physiological and biochemical markers during the 6-h perfusion period were comparable. However, perfusate lactate potassium levels were lower and ATP levels were higher in the PFCOC group. Radiologic assessment revealed significantly more lung infiltrates in the controls than in the PFCOC group (p = 0.04). In transplantation groups, perfusate glucose consumption was higher in the control group. Lactate levels were significantly lower in the PFCOC group (p = 0.02). Perfusate flavin mononucleotide (FMN) was significantly higher in the controls (p = 0.008). Post-transplant gas exchange was significantly better during the 4-h reperfusion period in the PFCOC group (p = 0.01). Plasma IL-8 and IL-12 levels were significantly lower in the PFCOC group (p = 0.01, p = 0.03, respectively). ATP lung tissue levels at the end of the transplantation were higher and myeloperoxidase (MPO) levels in lung tissue were lower in the PFCOC group compared to the control group. In the PFCOC group, TEM showed better tissue preservation and cellular viability. Conclusion: PFCOC application is safe during EVLP in lungs preserved 24 h at 4 °C. Although this strategy did not significantly affect the EVLP physiology, metabolic markers of the donor quality such as lactate production, glucose consumption, neutrophil infiltration and preservation of mitochondrial function were better in the PFCOC group. Following transplantation, PFCOC resulted in better graft function and TEM showed better tissue preservation, cellular viability and improved gas transport.

Experimental models closely representing in vivo conditions allow investigating mechanisms of resistance. Our aims were to establish a live-cell biobank of malignant pleural mesothelioma (MPM) samples and to obtain proof of principle that primary culture chemoresistant models, mimicking tumor progression observed in patients, can be obtained in vitro, providing a useful tool to investigate underlying mechanisms. Primary mesothelioma cultures were established from 235 samples between 2007 and 2014. Of two MPM patients, primary cultures obtained at different time points: at initial diagnosis, after neoadjuvant treatment at surgery and/or after tumor recurrence, were deeply investigated. Cells and corresponding tumor tissue were characterized by mesothelial protein and gene expression analysis. In addition, primary cultures from chemo naive patients were exposed to increasing doses of cisplatin/pemetrexed during three months and compared with non-treated cells in a cytotoxicity assay, and by selected profiling of senescence markers. In vitro chemoresistance in the primary mesothelioma cell cultures was associated with increased Thy1 (CD90) expression. Thy1 expression in MPM samples was significantly associated with poor overall survival in the TCGA MPM cohort. Our results illustrate that the establishment of a large live-cell MPM biobank contributes to a better understanding of therapy resistance observed in vivo, which eventually may lead to a more logical approach for developing new treatment strategies.

Malignant pleural mesothelioma (MPM) is a cancer associated with exposure to asbestos fibers, which accumulate in the pleural space, damage tissue and stimulate regeneration. Hedgehog signaling is a pathway important during embryonic mesothelium development and is inactivated in adult mesothelium. The pathway is reactivated in some MPM patients with poor clinical outcome, mainly mediated by the expression of the ligands. Nevertheless, mutations in components of the pathway have been observed in a few cases. Data from different MPM animal models and primary culture suggest that both autocrine and paracrine Hedgehog signaling are important to maintain tumor growth. Drugs inhibiting the pathway at the level of the smoothened receptor (Smo) or glioma-associated protein transcription factors (Gli) have been used mostly in experimental models. For clinical development, biomarkers are necessary for the selection of patients who can benefit from Hedgehog signaling inhibition.

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a debilitating disease, for which the underlying pathophysiological mechanisms have yet to be fully elucidated. Occurrence of a pulmonary embolism (PE) is a major risk factor for the development of CTEPH, with non-resolution of the thrombus being considered the main cause of CTEPH. Polymorphisms in the α-chain of fibrinogen have been linked to resistance to fibrinolysis in CTEPH patients, and could be responsible for development and disease progression. However, it is likely that additional genetic predisposition, as well as genetic and molecular alterations occurring as a consequence of tissue remodeling in the pulmonary arteries following a persistent PE, also play an important role in CTEPH. This review summarises the current knowledge regarding genetic differences between CTEPH patients and controls (with or without pulmonary hypertension). Mutations in BMPR2, differential gene and microRNA expression, and the transcription factor FoxO1 have been suggested to be involved in the processes underlying the development of CTEPH. While these studies provide the first indications regarding important dysregulated pathways in CTEPH (e.g., TGF-β and PI3K signaling), additional in-depth investigations are required to fully understand the complex processes leading to CTEPH.

We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).

Despite advances in malignant pleural mesothelioma therapy, life expectancy of affected patients remains short. The limited efficiency of treatment options is mainly caused by inter- and intra-tumor heterogeneity of mesotheliomas. This diversity can be observed at the morphological and molecular levels. Molecular analyses reveal a high heterogeneity (i) between patients; (ii) within different areas of a given tumor in terms of different clonal compositions; and (iii) during treatment over time. The aim of the present review is to highlight this diversity and its therapeutic implications.

The epithelioid and sarcomatoid histologic variants of malignant pleural mesothelioma (MPM) can be considered as E- and M-parts of the epithelial-mesenchymal transition (EMT) axis; the biphasic being an intermediate. EMT is associated with an increase of stem cell (SC) traits. We correlated the neural crest SC marker nestin and the EMT marker periostin with histology, type of neo-adjuvant chemotherapy (CT) and overall survival (OS) of MPM patients.Tumor tissues of a historic cohort 1 (320 patients) and an intended induction chemotherapy followed by extrapleural pneumonectomy (EPP) cohort 2 (145 patients) were immunohistochemically H-scored (intensity of immunoreactivity multiplied by frequency of stained cells). Paired chemo-naïve biopsies and -treated surgical specimens were available for 105/145 patients. CT included platinum/gemcitabine (Pla/Gem) or platinum/pemetrexed (Pla/Pem).Expression of any cytosolic nestin progressively increased from epithelioid to biphasic to sarcomatoid MPM in cohort 1, whereas the diagnostic markers calretinin and podoplanin decreased. In cohort 2, Pla/Pem CT increased the expression level of nestin in comparison to Pla/Gem, whereas the opposite was found for periostin. In Pla/Pem treated patients, nestin was higher in biphasic MPM compared to epithelioid. In addition to non-epithelioid histology, any expression of nestin in chemo-naïve biopsies (median overall survival: 22 vs. 17 months) and chemo-treated surgical specimens (18 vs. 12 months) as well as high periostin in biopsies (23 vs. 15 months) were associated with poor prognosis. In the multivariate survival analysis, any nestin expression in chemo-naïve biopsies proved to be an independent prognosticator against histology. In both pre- and post-CT situations, the combination of nestin or periostin expression with non-epithelioid histology was particularly/ dismal (all p-values