Mesothelioma: Scientific clues for prevention, diagnosis, and therapy.

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.

Defining and targeting tumor-associated macrophages in malignant mesothelioma.

Defining the ontogeny of tumor-associated macrophages (TAM) is important to develop therapeutic targets for mesothelioma. We identified two distinct macrophage populations in mouse peritoneal and pleural cavities, the monocyte-derived, small peritoneal/pleural macrophages (SPM), and the tissue-resident large peritoneal/pleural macrophages (LPM). SPM rapidly increased in tumor microenvironment after tumor challenge and contributed to the vast majority of M2-like TAM. The selective depletion of M2-like TAM by conditional deletion of the Dicer1 gene in myeloid cells (D-/-) promoted tumor rejection. Sorted SPM M2-like TAM initiated tumorigenesis in vivo and in vitro, confirming their capacity to support tumor development. The transcriptomic and single-cell RNA sequencing analysis demonstrated that both SPM and LPM contributed to the tumor microenvironment by promoting the IL-2-STAT5 signaling pathway, inflammation, and epithelial-mesenchymal transition. However, while SPM preferentially activated the KRAS and TNF-α/NFkB signaling pathways, LPM activated the IFN-γ response. The importance of LPM in the immune response was confirmed by depleting LPM with intrapleural clodronate liposomes, which abrogated the antitumoral memory immunity. SPM gene signature could be identified in pleural effusion and tumor from patients with untreated mesothelioma. Five genes, TREM2, STAB1, LAIR1, GPNMB, and MARCO, could potentially be specific therapeutic targets. Accordingly, Trem2 gene deletion led to reduced SPM M2-like TAM with compensatory increase in LPM and slower tumor growth. Overall, these experiments demonstrate that SPM M2-like TAM play a key role in mesothelioma development, while LPM more specifically contribute to the immune response. Therefore, selective targeting of monocyte-derived TAM may enhance antitumor immunity through compensatory expansion of tissue-resident TAM.

Endothelial Heterogeneity in the Response to Autophagy Drives Small Vessel Muscularization in Pulmonary Hypertension.

BACKGROUND: Endothelial cell (EC) apoptosis and proliferation of apoptosis-resistant cells is a hallmark of pulmonary hypertension (PH). Yet, why some ECs die and others proliferate and how this contributes to vascular remodeling is unclear. We hypothesized that this differential response may: (1) relate to different EC subsets, namely pulmonary artery (PAECs) versus microvascular ECs (MVECs); (2) be attributable to autophagic activation in both EC subtypes; and (3) cause replacement of MVECs by PAECs with subsequent distal vessel muscularization. METHODS: EC subset responses to chronic hypoxia were assessed by single-cell RNA sequencing of murine lungs. Proliferative versus apoptotic responses, activation, and role of autophagy were assessed in human and rat PAECs and MVECs, and in precision-cut lung slices of wild-type mice or mice with endothelial deficiency in the autophagy gene Atg7 (Atg7EN-KO). Abundance of PAECs versus MVECs in precapillary microvessels was assessed in lung tissue from patients with PH and animal models on the basis of structural or surface markers. RESULTS: In vitro and in vivo, PAECs proliferated in response to hypoxia, whereas MVECs underwent apoptosis. Single-cell RNA sequencing analyses support these findings in that hypoxia induced an antiapoptotic, proliferative phenotype in arterial ECs, whereas capillary ECs showed a propensity for cell death. These distinct responses were prevented in hypoxic Atg7EN-KO mice or after ATG7 silencing, yet replicated by autophagy stimulation. In lung tissue from mice, rats, or patients with PH, the abundance of PAECs in precapillary arterioles was increased, and that of MVECs reduced relative to controls, indicating replacement of microvascular by macrovascular ECs. EC replacement was prevented by genetic or pharmacological inhibition of autophagy in vivo. Conditioned medium from hypoxic PAECs yet not MVECs promoted pulmonary artery smooth muscle cell proliferation and migration in a platelet-derived growth factor-dependent manner. Autophagy inhibition attenuated PH development and distal vessel muscularization in preclinical models. CONCLUSIONS: Autophagic activation by hypoxia induces in parallel PAEC proliferation and MVEC apoptosis. These differential responses cause a progressive replacement of MVECs by PAECs in precapillary pulmonary arterioles, thus providing a macrovascular context that in turn promotes pulmonary artery smooth muscle cell proliferation and migration, ultimately driving distal vessel muscularization and the development of PH.

Long noncoding RNA GATA2-AS1 augments endothelial hypoxia inducible factor 1-α induction and regulates hypoxic signaling.

Vascular endothelial cells form the inner cellular lining of blood vessels and have myriad physiologic functions including angiogenesis and response to hypoxia. We recently identified a set of endothelial cell (EC)-enriched long noncoding RNAs (lncRNAs) in differentiated human primary cell types and described the role of the STEEL lncRNA in angiogenic patterning. We sought to further understand the role of EC-enriched lncRNAs in physiologic adaptation of the vascular endothelium. In this work, we describe an abundant, cytoplasmic, and EC-enriched lncRNA, GATA2-AS1, that is divergently transcribed from the EC-enriched developmental regulator, GATA2. While GATA2-AS1 is largely coexpressed with GATA2 in ECs, GATA2-AS1 and GATA2 appear to be complementary rather than synergistic as they have mostly distinct target genes. Common single nucleotide variants in GATA2-AS1 exons are associated with early-onset coronary artery disease and decreased expression of GATA2-AS1 in endothelial cell lines. In most cells, HIF1-α is central to the transcriptional response to hypoxia, while in ECs, both HIF1-α and HIF2-α are required to coordinate an acute and chronic response, respectively. In this setting, GATA2-AS1 contributes to the "HIF switch" and augments HIF1-α induction in acute hypoxia to regulate HIF1-α/HIF2-α balance. In hypoxia, GATA2-AS1 orchestrates HIF1-α-dependent induction of the glycolytic pathway and HIF1-α-independent maintenance of mitochondrial biogenesis. Similarly, GATA2-AS1 coordinates both metabolism and "tip/stalk" cell signaling to regulate angiogenesis in hypoxic ECs. Furthermore, we find that GATA2-AS1 expression patterns are perturbed in atherosclerotic disease. Together, these results define a role for GATA2-AS1 in the EC-specific response to hypoxia.

JSI-124 inhibits cell proliferation and tumor growth by inducing autophagy and apoptosis in murine malignant mesothelioma.

Malignant pleural mesothelioma (MPM), mainly caused by asbestos exposure, has a poor prognosis and lacks effective treatment compared with other cancer types. The intracellular transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed and hyperactivated in most human cancers. In this study, the role of STAT3 in murine MPM was examined. Inhibition of the Janus kinase 2 (JAK2)/STAT3 pathway with the selective inhibitor JSI-124 has an antitumor effect in murine MPM. Specifically, we demonstrated that JSI-124 inhibits murine MPM cell growth and induces apoptotic and autophagic cell death. Exposure of RN5 and AB12 cells to JSI-124 resulted in apoptosis via the Bcl-2 family of proteins. JSI-124 triggered autophagosome formation, accumulation, and conversion of LC3I to LC3II. Autophagy inhibitors, Chloroquine (CQ) and Bafilomycin A1 (Baf-A1), inhibited autophagy and sensitized RN5 and AB12 cells to JSI-124-induced apoptosis. Our data indicate that JSI-124 is a promising therapeutic agent for MPM treatment.

Osteosarcoma emboli presenting as chronic thromboembolic pulmonary hypertension in a child.

A 13-year-old girl presented with hypoxemia during adjuvant chemotherapy for an osteosarcoma of the left distal femur. She underwent an amputation complicated by a post-operative pulmonary embolism (PE). Three months post-operatively, she was admitted to hospital with severe hypoxemia and diagnosed with pulmonary hypertension on echocardiogram in the context of extensive bilateral PE on computed tomography. She was planned for elective pulmonary thromboendarterectomy, but rapidly deteriorated requiring emergent surgery. At the time of surgery, she was found to have extensive tumor emboli throughout both pulmonary arteries. She recovered well post-operatively but died 2 months later from progressive disease.

Prognostic Value of EMT Gene Signature in Malignant Mesothelioma.

Malignant mesothelioma (MESO) consists of epithelioid, biphasic, and sarcomatoid subtypes with different epithelial-mesenchymal transition (EMT) phenotypes. We previously identified a panel of four MESO EMT genes correlating with an immunosuppressive tumor microenvironment and poor survival. In this study, we investigated the correlation between these MESO EMT genes, the immune profile, and the genomic and epigenomic alterations to identify potential therapeutic targets to prevent or reverse the EMT process. Using multiomic analysis, we observed that the MESO EMT genes were positively correlated with hypermethylation of epigenetic genes and loss of CDKN2A/B expression. MESO EMT genes such as COL5A2, ITGAV, SERPINH1, CALD1, SPARC, and ACTA2 were associated with upregulation of TGF-ß signaling, hedgehog signaling, and IL-2-STAT5 signaling and downregulation of the IFN-α and IFN-γ response. Immune checkpoints such as CTLA4, CD274 (PD-L1), PDCD1LG2 (PD-L2), PDCD1 (PD-1), and TIGIT were upregulated, while LAG3, LGALS9, and VTCN1 were downregulated with the expression of MESO EMT genes. CD160, KIR2DL1, and KIR2DL3 were also broadly downregulated with the expression of MESO EMT genes. In conclusion, we observed that the expression of a panel of MESO EMT genes was associated with hypermethylation of epigenetic genes and loss of expression of CDKN2A and CDKN2B. Expression of MESO EMT genes was associated with downregulation of the type I and type II IFN response, loss of cytotoxicity and NK cell activity, and upregulation of specific immune checkpoints, as well as upregulation of the TGF-ß1/TGFBR1 pathway.

Outcomes of lung transplantation from organ donation after medical assistance in dying: First North American experience.

Over 2.5% of deaths in Canada occur as a result from medical assisting in dying (MAID), and a subset of these deaths result in organ donation. However, detailed outcomes of lung transplant recipients using these donors is lacking. This is a retrospective single center cohort study comparing lung transplantation outcomes after donation using MAID donors compared to neurologically determined death and controlled donation after circulatory death (NDD/cDCD) donors from February 2018 to July 2021. Thirty-three patients received lungs from MAID donors, and 560 patients received lungs from NDD/cDCD donors. The donor diagnoses leading to MAID provision were degenerative neurological diseases (n = 33) and end stage organ failure (n = 5). MAID donors were significantly older than NDD/cDCD donors (56 [IQR 49-64] years vs. 48 [32-59]; p = .0009). Median ventilation period and 30 day mortality were not significantly different between MAID and NDD/cDCD lungs recipients (ventilation: 1 day [1-3] vs 2 days [1-3]; p = .37, deaths 0% [0/33] vs. 2% [11/560], p = .99 respectively). Intermediate-term outcomes were also similar. In summary, for lung transplantation using donors after MAID, recipient outcomes were excellent. Therefore, where this practice is permitted, donation after MAID should be strongly considered for lung transplantation as a way to respect donor wishes while substantially improving outcomes for recipients with end-stage lung disease.

Expression of phosphorylated ribosomal protein S6 in mesothelioma patients - correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project.

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies.

Role of extracorporeal membrane oxygenation and surgical embolectomy in acute pulmonary embolism.

PURPOSE OF REVIEW: Surgery is an important option to consider in patients with massive and submassive pulmonary emboli. Earlier intervention, better patient selection, improved surgical techniques and the use of veno-arterial extracorporeal membrane oxygenation (VA ECMO) have contributed to improve the safety of surgery for pulmonary emboli. RECENT FINDINGS: VA ECMO is rapidly changing the initial management of patients with massive pulmonary emboli, providing an opportunity for stabilization and optimization before intervention. The early and long-term consequences of acute pulmonary emboli are better understood, in particular with regard to the risks of chronic thromboembolic pulmonary hypertension (CTEPH), an entity that should be identified in the acute setting as much as possible. The presence of chronic thromboembolic pulmonary disease can be associated with persistent haemodynamic instability despite removal of the acute thrombi, particularly if pulmonary hypertension is established. The pulmonary embolism response team (PERT) is an important component in the management of massive and submassive acute pulmonary emboli to determine the best treatment options for each patient depending on their clinical presentation. SUMMARY: Three types of surgery can be performed for pulmonary emboli depending on the extent and degree of organization of the thrombi (pulmonary embolectomy, pulmonary thrombo-embolectomy and pulmonary thrombo-endarterectomy). Other treatment options in the context of acute pulmonary emboli include thrombolysis and catheter-directed embolectomy. Future research should determine how best to integrate VA ECMO as a bridging strategy to recovery or intervention in the treatment algorithm of patients with acute massive pulmonary emboli.

Foxp3+ Regulatory T Cell Depletion after Nonablative Oligofractionated Irradiation Boosts the Abscopal Effects in Murine Malignant Mesothelioma.

Increasing evidence indicates that local hypofractionated radiotherapy (LRT) can elicit both immunogenic and immunosuppressive local and systemic immune responses. We thus hypothesized that blockade of LRT-induced immunosuppressive responses could augment the antitumor effects and induce an abscopal response. In this study, we found that the upregulation of Foxp3+ regulatory T cells (Tregs) in the mesothelioma tumor microenvironment after nonablative oligofractionated irradiation significantly limited the success of irradiation. Using DEREG mice, which allow conditional and efficient depletion of Foxp3+ Tregs by diphtheria toxin injection, we observed that transient Foxp3+ Treg depletion immediately after nonablative oligofractionated irradiation provided synergistic local control and biased the T cell repertoire toward central and effector memory T cells, resulting in long-term cure. Furthermore, this combination therapy showed significant abscopal effect on the nonirradiated tumors in a concomitant model of mesothelioma through systemic activation of cytotoxic T cells and enhanced production of IFN-γ and granzyme B. Although local control was preserved with one fraction of nonablative irradiation, three fractions were required to generate the abscopal effect. PD-1 and CTLA-4 were upregulated on tumor-infiltrating CD4+ and CD8+ T cells in irradiated and nonirradiated tumors, suggesting that immune checkpoint inhibitors could be beneficial after LRT and Foxp3+ Treg depletion. Our findings are applicable to the strategy of immuno-radiotherapy for generating optimal antitumor immune responses in the clinical setting. Targeting Tregs immediately after a short course of irradiation could have a major impact on the local response to irradiation and its abscopal effect.

Surgery for malignant pleural mesothelioma after radiotherapy (SMART): final results from a single-centre, phase 2 trial.

BACKGROUND: A novel approach for managing malignant pleural mesothelioma, surgery for mesothelioma after radiotherapy (SMART), consisting of a short accelerated course of high-dose, hemithoracic, intensity modulated radiotherapy (IMRT) followed by extrapleural pneumonectomy was developed. The aim of this study was to evaluate the clinical feasibility of the SMART protocol. METHODS: In this single-centre, phase 2 trial, patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, with histologically proven, resectable, cT1-3N0M0 disease who had previously untreated malignant pleural mesothelioma were eligible for inclusion. Patients received 25 Gy in five daily fractions over 1 week to the entire ipsilateral hemithorax with a concomitant 5 Gy boost to high risk areas followed by extrapleural pneumonectomy within 1 week. Adjuvant chemotherapy was offered to patients with ypN+ disease on final pathology. The primary endpoint was feasibility, which was defined as the number of patients with 30-day perioperative treatment-related death (grade 5 events) or morbidity (grade 3 or 4 events). A key secondary endpoint was cumulative incidence of distant recurrence. The final analysis was done on an intention-to-treat basis (including all eligible patients). This trial is registered with ClinicalTrials.gov, NCT00797719. FINDINGS: Between Nov 1, 2008, and Oct 31, 2019, 102 patients were enrolled onto the trial and 96 eligible patients were treated with SMART on protocol and included in the analysis. Extrapleural pneumonectomy was done at a median of 5 days (range 2-12) after completing IMRT. 47 (49%) patients had 30-day perioperative grade 3-4 events and one (1%) patient died within 30 days perioperatively (grade 5 event; pneumonia). After a median follow-up of 46·8 months (IQR 13·4-61·2), the 5-year cumulative incidence of distant recurrence was 62 (63·3% [95% CI 52·3-74·4]). The most common first sites of recurrence were the contralateral chest (33 [46%] of 72 patients) and the peritoneal cavity (32 [44%]). INTERPRETATION: Results from this study suggest that extrapleural pneumonectomy after radiotherapy can be done with good early and long-term results. However, minimising grade 4 events on the protocol is technically demanding and might affect survival beyond the post-operative period. FUNDING: Princess Margaret Hospital Foundation Mesothelioma Research Fund.

Initial lung transplantation experience with uncontrolled donation after cardiac death in North America.

Uncontrolled donation after cardiac death (uDCD) has the potential to ameliorate the shortage of suitable lungs for transplant. To date, no lung transplant data from these donors are available from North America. We describe the successful use of these donors using a simple method of in situ lung inflation so that the organ can be protected from warm ischemic injury. Forty-four potential donors were approached, and family consent was obtained in 30 cases (68%). Of these, the lung transplant team evaluated 16 uDCDs on site, and 14 were considered for transplant pending ex vivo lung perfusion assessment. Five lungs were ultimately used for transplant (16.7% use rate from consented donors). The mean warm ischemic time was 2.8 hours. No primary graft dysfunction grade 3 was observed at 24, 48, or 72 hours after transplant. Median intensive care unit stay was 5 days (range: 2-78 days), and median hospital stay was 17 days (range: 8-100 days). The 30-day mortality was 0%. Four of 5 patients are alive at a median of 651 days (range: 121-1254 days) with preserved lung function. This study demonstrates the proof of concept and the potential for uDCD lung donation using a simple donor intervention.

Malignant mesothelioma in situ: morphologic features and clinical outcome.

The existence of an in situ phase of malignant mesothelioma has long been postulated but until recently has been impossible to prove. Here we describe ten patients with mesothelioma in situ, defined by a single layer of surface mesothelial cells showing loss of BAP1 nuclear immunostaining, no evidence of tumor by imaging and/or by direct examination of the pleura/peritoneum, and no invasive mesothelioma developing for at least 1 year. Nine cases were pleural and one peritoneal. Most patients were biopsied for repeated effusions of unknown etiology; in two patients mesothelioma in situ was found incidentally in lung cancer resections. In addition to surface mesothelium with BAP1 loss, one case had a surface papillary proliferation with BAP1 loss, and two cases had a small (few millimeter) nodule with BAP1 loss. CDKN2A was deleted by FISH in one of eight cases. Methylthioadenosine phosphorylase showed partial loss in the surface mesothelium by immunohistochemistry in three cases. Invasive malignant mesothelioma developed in seven patients with time between biopsy and invasive disease from 12 to 92 (median 60) months. Invasive mesothelioma has not developed in the other three patients at 12, 57, and 120 months, but the latter patient, who has pleural plaques, still has repeated pleural effusions, probably representing a so-called "benign asbestos effusion." We conclude that mesothelioma in situ, as diagnosed using the criteria outlined above, is associated with a high risk of developing invasive mesothelioma, but typically over a relatively protracted time, so that curable interventions maybe possible.

Localized malignant mesothelioma, an unusual and poorly characterized neoplasm of serosal origin: best current evidence from the literature and the International Mesothelioma Panel.

Localized malignant mesotheliomas (LMM) is an uncommon and poorly recognized neoplasm. Its pathologic diagnosis is often surprising in patients with serosal/subserosal based localized tumors that are clinically suspicious for metastatic lesions or primary sarcomas. Once a tumor is diagnosed as "mesothelioma", LMM is often mistaken for diffuse malignant mesothelioma (DMM). Best currently available evidence about LMM was collected from the literature and cases diagnosed by members of the International Mesothelioma Panel (IMP). One hundred and one (101) LMM have been reported in the English literature. Patients had localized tumors with identical histopathologic features to DMM. Patients ranged in age from 6 to 82 years; 75% were men. Most (82%) of the tumors were intrathoracic. Others presented as intrahepatic, mesenteric, gastric, pancreatic, umbilical, splenic, and abdominal wall lesions. Tumors varied in size from 0.6 to 15 cm. Most patients underwent surgical resection and/or chemotherapy or radiation therapy. Median survival in a subset of patients was 29 months. Seventy two additional LMM from IMP institutions ranged in age from 28 to 95 years; 58.3% were men. Sixty tumors (83.3%) were intrathoracic, others presented in intraabdominal sites. Tumors varied in size from 1.2 to 19 cm. Median survival for 51 cases was 134 months. Best evidence was used to formulate guidelines for the diagnosis of LMM. It is important to distinguish LMM from DMM as their treatment and prognosis is different. A multidisciplinary approach is needed for the diagnosis of LMM as it shows identical histopathology and immunophenotype to DMM.

Systemic Therapy Use and Outcomes After Relapse from Preoperative Radiation and Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma.

BACKGROUND: Multimodality therapy with preoperative radiation (RT) followed by extrapleural pneumonectomy (EP) for patients with operable malignant pleural mesothelioma (MPM) has demonstrated encouraging results. At relapse, there are few data on the tolerance and efficacy of systemic therapies after prior multimodality therapy. MATERIALS AND METHODS: We conducted a retrospective analysis of patients with relapsed MPM after RT and EPP ± adjuvant chemotherapy to determine overall survival (OS; date of relapse to death) and the proportion of patients that received systemic therapy and associated response rate (RR). OS was estimated using Kaplan-Meier method and potential prognostic variables were examined. RESULTS: Fifty-three patients were included (2008-2016). Median OS was 4.8 months (median follow-up 4.4 months, range 0.03-34.8). Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2, disease-free interval (DFI) <1 year, and hemoglobin ≤110 g/L at recurrence were associated with worse prognosis. Thirty-six percent of patients received any systemic therapy, whereas it was omitted in 62% because of poor PS. RR was 15% (0 complete responses, 15% partial responses) in 13 individuals with response-evaluable disease. Therapy was discontinued because of toxicity (6/15) or disease progression (5/15), and median number of cycles was four. CONCLUSION: Patients with relapsed MPM following RT and EPP, especially those with ECOG PS ≥2, DFI <1 year, and hemoglobin ≤110 g/L at recurrence, have poor prognosis and low RR to first-line systemic therapy. Earlier detection and novel diagnostic markers of relapse as well as potential neoadjuvant or adjuvant systemic therapy should be investigated in future studies. IMPLICATIONS FOR PRACTICE: The results of this study have reinforced the importance of careful selection of appropriate candidates for this combined-modality approach and favor prompt detection of recurrence with early and regular postoperative imaging and biopsy of suspected relapsed disease along with rapid initiation of systemic therapy even in patients with very low burden of disease. Furthermore, with the emergence of new systemic agents targeting different histological subtypes of malignant pleural mesothelioma, histological sampling of recurrence could inform therapeutic decisions in the future.

Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.

Intensive care of patients with pulmonary hypertension (PH) and right-sided heart failure includes treatment of factors causing or contributing to heart failure, careful fluid management, and strategies to reduce ventricular afterload and improve cardiac function. Extracorporeal membrane oxygenation (ECMO) should be considered in distinct situations, especially in candidates for lung transplantation (bridge to transplant) or, occasionally, in patients with a reversible cause of right-sided heart failure (bridge to recovery). ECMO should not be used in patients with end-stage disease without a realistic chance for recovery or for transplantation. For patients with refractory disease, lung transplantation remains an important treatment option. Patients should be referred to a transplant centre when they remain in an intermediate- or high-risk category despite receiving optimised pulmonary arterial hypertension therapy. Meticulous peri-operative management including the intra-operative and post-operative use of ECMO effectively prevents graft failure. In experienced centres, the 1-year survival rates after lung transplantation for PH now exceed 90%.

Association of two BRM promoter polymorphisms and smoking status with malignant pleural mesothelioma risk and prognosis.

Brahma (BRM), of the SWI/SNF complex, has two 6 to 7 bp insertion promoter polymorphisms (BRM-741/BRM-1321) that cause epigenetic BRM suppression, and are associated with risk of multiple cancers. BRM polymorphisms were genotyped in malignant pleural mesothelioma (MPM) cases and asbestos-exposed controls. Multivariable logistic regression (risk) and Cox regression (prognosis) were performed, including stratified analyses by smoking status to investigate the effect of polymorphisms on MPM risk and prognosis. Although there was no significant association overall between BRM-741/BRM-1321 and risk in patients with MPM, a differential effect by smoking status was observed (P-interaction < .001), where homozygous variants were protective (aOR of 0.18-0.28) in ever smokers, while never smokers had increased risk when carrying homozygous variants (aOR of 2.7-4.4). While there was no association between BRM polymorphisms and OS in ever-smokers, the aHR of carrying homozygous-variants of BRM-741, BRM-1321 or both were 4.0 to 8.6 in never-smokers when compared to wild-type carriers. Mechanistically, lower mRNA expression of BRM was associated with poorer general cancer prognosis. Electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (ChIP) revealed high BRM insertion variant homology to MEF2 regulatory binding sites. ChIP experimentation confirmed MEF2 binding only occurs in the presence of insertion variants. DNA-affinity purification assays revealed YWHA scaffold proteins as vital to BRM mRNA expression. Never-smokers who carry BRM homozygous variants have an increased chance of developing MPM, which results in worse prognosis. In contrast, in ever-smokers, there may be a protective effect, with no difference in overall survival. Mechanisms for the interaction between BRM and smoking require further study.

Frailty assessment prior to thoracic surgery for lung or esophageal cancer: a feasibility study.

BACKGROUND: Frailty assessment has not been thoroughly assessed in thoracic surgery. Our primary objective was to assess the feasibility of comprehensive frailty testing prior to lung and esophageal surgery for cancer. The secondary objective was to assess the utility of frailty indices in risk assessment prior to thoracic surgery. METHODS: Prospectively recruited patients completed multiple physiotherapy tests (6-min walk, gait speed, hand-grip strength), risk stratification (Charlson Comorbidity Index, Revised Cardiac Risk Index, Modified Frailty Index), and quality of life questionnaires. Lean psoas area was also assessed by a radiologist using positron emission tomography/computed tomography scans. Data was analyzed using Fisher's exact, Mann-Whitney U and independent t tests. RESULTS: The feasibility of comprehensive frailty assessment was assessed over a 4-month period among 40 patients (esophagus n = 20; lung n = 20). Risk stratification questionnaires administered in clinic had 100% completion rates. Physiotherapy testing required a trained physiotherapist and an additional visit to the pre-admission clinic; these tests proved difficult to coordinate and had lower completion rates (63-75%). Although most measures were not significantly associated with occurrence of complications, the Modified Frailty Index approached statistical significance (p = 0.06). CONCLUSIONS: Frailty assessment is feasible in the pre-operative outpatient setting and had a high degree of acceptance among surgeons and patients. Of the risk stratification questionnaires, the Modified Frailty Index may be useful in predicting outcomes as per this feasibility study. Pre-operative frailty assessment can identify vulnerable oncology patients to aid in treatment planning with the goal of optimizing clinical outcomes and resource allocation.