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Malignant pleural mesothelioma (MPM) is a rare form of cancer that is associated with asbestos exposure. Unfortunately, current therapies have limited efficacy. Previous studies have indicated that curcumin exerts antiproliferative and antitumor effects, and has low toxicity. The present study aimed to evaluate the anticancer effects of curcumin on the RN5 MPM cell line. The inhibitory effects of curcumin on cell viability were determined using the sulforhodamine B assay. In addition, cell cycle progression was analyzed by propidium iodide (PI) staining and flow cytometry, and curcumin-induced apoptosis was measured by Annexin V/PI double staining. The translocation of apoptosis-inducing factor (AIF) was assessed by western blotting and immunofluorescence, and the expression levels of the phosphoinositide 3-kinase (PI3K)-AKT serine/threonine kinase (Akt)-mammalian target of rapamycin (mTOR) signaling pathway proteins and mitochondria-associated proteins were evaluated by western blotting. In vivo antitumor effects were evaluated in a subcutaneous murine model. Briefly, tumors were harvested from the mice, and immunohistochemistry was conducted to evaluate cell proliferation, apoptosis and angiogenesis. The results indicated that curcumin inhibited RN5 cell viability and induced apoptotic cell death. In addition the findings suggested that curcumin-induced cell apoptosis occurred via the mitochondrial pathway, and caspase-independent and AIF-dependent pathways. Further analysis revealed that curcumin may act as a PI3K-Akt-mTOR signaling pathway inhibitor by downregulating PI3K, p-Akt, p-mTOR and p-p70 ribosomal protein S6 kinase. Furthermore, curcumin inhibited tumor angiogenesis in vivo. In conclusion, curcumin may be potent enough to be developed as a novel therapeutic agent for the treatment of MPM.

The study aim is to compare the diagnostic yield, safety, and cost of outpatient awake thoracoscopy (AT) with video-assisted thoracoscopic surgery (VATS) pleural biopsy in undiagnosed pleural effusions.The diagnostic yield of pleural biopsy performed by AT or VATS in patients with undiagnosed exudative pleural effusions at a tertiary thoracic surgery center in Canada between 2011 and 2015 was retrospectively evaluated. Test sensitivity, specificity, positive predictive value, and negative predictive value were compared. Procedure safety, hospital length of stay, additional pleural-based interventions, and procedure-related costs were compared.Patients underwent either AT (n = 78) or VATS (n = 99) during the study period. Sensitivity, specificity, positive predictive value, and negative predictive value were 85%, 100%, 100%, and 79% for AT and 93%, 94%, 99%, and 76% for VATS, with no significant difference in diagnostic test performance. There was no difference in the rate of major complications (2 AT [2.6%] versus 4 VATS [4.0%], p = 0.696), minor complications (14 AT [17.9%] versus 16 VATS [16.2%], p = 0.841) or need for additional pleural-based procedures (20 AT [25.6%] versus 18 VATS [18.2%], p = 0.270). The VATS was associated with longer median hospital stay (VATS 3 days [interquartile range: 1 to 4] versus AT 0 days [interquartile range: 0 to 1], z = 6.98, p0.001) and a higher procedure-related average cost (VATS Canadian dollars $7,962 [95% confidence interval: $7,134 to $8,790] versus AT Canadian dollars $2,815 [95% confidence interval: $2,010 to $3,620], p0.001).Awake thoracoscopy and VATS have similar diagnostic yield and safety profiles in the assessment of undiagnosed pleural effusions; however, AT is associated with shorter length of stay and lower average per-procedure cost. In the appropriate clinical setting, AT may be the diagnostic test of choice.

The mortality rate for individuals on the wait list for lung transplant is 15% to 25%, and still only 20% of lungs from multiorgan donors are used for lung transplant. The lung donor pool may be increased by assessing and reconditioning high-risk extended criteria donor lungs with ex vivo lung perfusion (EVLP), with similar short-term outcomes.To assess the long-term outcomes of transplant recipients of donor lungs treated with EVLP.This retrospective cohort single-center study was conducted from August 1, 2008, to February 28, 2017, among 706 recipients of donor lungs not undergoing EVLP and 230 recipients of donor lungs undergoing EVLP.Donor lungs undergoing EVLP.The incidence of chronic lung allograft dysfunction and allograft survival during the 10-year EVLP era were the primary outcome measures. Secondary outcomes included donor characteristics, maximum predicted percentage of forced expiratory volume in 1 second, acute cellular rejection, and de novo donor-specific antibody development.This study included 706 patients (311 women and 395 men; median age, 50 years [interquartile range, 34-61 years]) in the non-EVLP group and 230 patients (85 women and 145 men; median age, 46 years [interquartile range, 32-55 years]) in the EVLP group. The EVLP group donors had a significantly lower mean (SD) Pao2:fraction of inspired oxygen ratio than the non-EVLP group donors (348 [108] vs 422 [88] mm Hg; P .001), higher prevalence of abnormal chest radiography results (135 of 230 [58.7%] vs 349 of 706 [49.4%]; P = .02), and higher proportion of smoking history (125 of 204 [61.3%] vs 322 of 650 [49.5%]; P = .007). More recipients in the EVLP group received single-lung transplants (62 of 230 [27.0%] vs 100 of 706 [14.2%]; P .001). There was no significant difference in time to chronic lung allograft dysfunction between the EVLP and non-EVLP group (70% vs 72% at 3 years; 56% vs 56% at 5 years; and 53% vs 36% at 9 years; log-rank P = .68) or allograft survival between the EVLP and non-EVLP groups (73% vs 72% at 3 years; 62% vs 58% at 5 years; and 50% vs 44% at 9 years; log-rank P = .97) between the 2 groups. All secondary outcomes were similar between the 2 groups.Since 2008, 230 of 936 lung transplants (24.6%) in the Toronto Lung Transplant Program were performed after EVLP assessment and treatment. Use of EVLP-treated lungs led to an increase in the number of patients undergoing transplantation, with comparable long-term outcomes.

Cancer is an independent major risk factor for venous thromboembolism (VTE), which is the second leading cause of death in medically and surgically treated patients with cancer (1-5). The association between VTE and lung cancer has been reported more than 20 years ago (6,7).

The role of extracorporeal life support (ECLS) has expanded rapidly over the past 15 years to become an important tool in advanced general thoracic surgery practice. Intra-operative and in some cases continued post-operative ECLS is redefining the scope of complex surgical care. ECLS encompasses a spectrum of temporary mechanical support that may remove CO2, oxygenate or provide hemodynamic support or a combination thereof. The most common modalities used in general thoracic surgery include extracorporeal membrane oxygenation (ECMO), interventional lung assist device (iLA® Novalung®, Heilbronn, Germany), and extracorporeal CO2 removal (ECCO2R). The ECMO and Novalung® devices can be used in different modes for the short term or long-term support depending on the situation. In this review, the principles and current applications of ECLS in general thoracic surgery are presented.

// Mathieu Francois Derouet 1 , Eugenia Dakpo 1 , Licun Wu 1 , Guan Zehong 1 , James Conner 4 , Shaf Keshavjee 1, 2 , Marc de Perrot 1, 2 , Thomas Waddell 1, 2 , Elena Elimova 3 , Jonathan Yeung 1, 2 and Gail Elizabeth Darling 1, 2 1 Latner Thoracic Surgery Research Laboratories, Princess Margaret Cancer Research Tower, University Health Network, Toronto, Ontario, Canada 2 Department of Surgery, Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada 3 Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada 4 Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada Correspondence to: Mathieu Francois Derouet, email: mderouet@uhnresearch.ca Gail Elizabeth Darling, email: gdarling@uhn.ca Keywords: esophageal adenocarcinoma; miR-145; c-Myc; integrins; metastasis Abbreviations: CLL: Chronic Lymphocytic Leukemia; EAC: Esophageal Adenocarcinoma; FCS: Foetal Calf Serum; HRP: Horseradish Peroxidase; PVDF: Polyvinylidene Received: June 07, 2017 Accepted: February 21, 2018 Epub: March 08, 2018 Published: March 16, 2018 ABSTRACT Adenocarcinoma of the esophagus is increasing in frequency and is the 6th most common cause of cancer death in North America. In adenocarcinoma cell lines, we have previously demonstrated that expression of miR-145, leads to enhanced invasion, resistance to anoikis and better attachment to fibronectin in esophageal adenocarcinoma. In contrast, expression of miR-145 acts as a tumor suppressor in squamous cell carcinoma. The molecular mechanisms responsible for the oncogenic effects of miR-145 were investigated. In this report, we demonstrate that we can partially recreate the miR-145 effects in EAC by knock down of the expression of c-Myc, which is one of the targets of miR-145. Knocking down of c-Myc expression resulted in upregulation of integrin subunits α5 and β3. Finally, we demonstrated that integrin α5 expression correlates to fibronectin attachment potential whereas integrin β3 expression correlates with resistance to anoikis and invasion potential. Finally, we demonstrate that expression of miR-145 in esophageal adenocarcinoma cell line (SK-GT-4) enhances tumor growth and metastasis in a NOD/SCID xenograft model. Overall, the oncogenic potential of miR-145 in EAC appears to be mediated by downregulation of c-Myc leading to the expression of integrins subunits α5 and β3.

Background: Malignant pleural mesothelioma (MESO) has a poor prognosis despite aggressive treatment with surgery, radiation and chemotherapy, and novel therapeutic approaches are needed. IRF3 is a downstream molecule of the cGAS/STING signaling pathway, but its roles have not been investigated in MESO. Methods: Various murine mesothelioma cell lines were inoculated into wild type (WT) and IRF3 knockout (IRF3KO) mice to compare tumor growth. AE17-bearing mice were treated with local radiotherapy (LRT) to evaluate the effect on tumor growth, and immune cell infiltration was analyzed by flow cytometry 20 days after tumor inoculation. TCGA data were used to examine the relationship between mRNA expression of IRF3 and genes of the cGAS/STING signaling cascade on prognosis in MESO. Correlations between gene expression of IRF3, cGAS/STING signaling pathway, and immune checkpoints were analyzed in TCGA MESO and our scRNA-Seq data from MESO patients. Results: In mouse mesothelioma models, AK7, RN5 and ZiP3 were completely rejected in IRF3KO mice 20 days after the tumor challenge. AE17tumor volume was slightly larger than WT mice around day 10 before shrinking and becoming significantly smaller than WT mice on day 20. LRT accelerated tumor shrinkage of AE17 tumors in IRF3KO mice. Compared with WT mice, the number of macrophages infiltrating the tumor of IRF3KO mice was significantly reduced, and CD4+ T cells and CD8+IFNγ+ T cells were significantly increased. TCGA data showed that IRF3 expression was an unfavorable prognostic factor in MESO patients. IRF3 expression, the cGAS/STING signaling pathway, and immune checkpoints were positively correlated. Conclusion: IRF3 could play a critical role in the tumor immune microenvironment of MESO.

Summary Malignant pleural mesothelioma is an aggressive disease that continues to be associated with poor outcomes. Although, traditionally this disease is considered to be resistant to radiotherapy, more recent evidence suggests that radiotherapy can produce positive outcomes. Over the past 15 years, the development of new, highly conformal radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), has enabled investigators to optimise the delivery of high-dose radiotherapy to the whole of the hemithorax. Prospective single-arm trials have shown that the median survival of patients who have completed high-dose hemithoracic radiotherapy after extrapleural pneumonectomy could reach 23·9–39·4 months independent of the chemotherapeutic response, suggesting that IMRT could potentially have an intrinsic benefit to this subset of patients. These observations have led to a change in practice, with the introduction of adjuvant pleural IMRT after pleurectomy-decortication and the development of induction-accelerated hemithoracic IMRT followed by extrapleural pneumonectomy. This Review focuses on recent observations on the role of radiotherapy in the treatment of malignant pleural mesothelioma, with particular emphasis on the results of clinical trials that evaluate the role of high-dose hemithoracic radiotherapy.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed potential complication of acute or recurrent pulmonary thromboembolic disease. Multiple studies suggest that up to 5% of patients with acute pulmonary thromboembolic disease go on to develop CTEPH. The prognosis of untreated CTEPH is poor, but advances in medical and surgical treatments over the past few decades have improved patient outcomes. The gold standard and curative treatment for CTEPH is pulmonary endarterectomy; however, some patients are inoperable and others who have undergone pulmonary endarterectomy experience persistent or recurrent pulmonary hypertension despite medical therapy. In recent years, balloon pulmonary angioplasty has emerged as a primary and adjunctive treatment for these CTEPH patients at expert or specialized centers. This review outlines an approach to balloon pulmonary angioplasty for CTEPH, including clinical presentation and evaluation; patient selection and indications; treatment planning; equipment and technique; overcoming technical challenges; recognition and management of complications; postprocedural care and clinical follow-up; and expected outcomes.

Background Despite guidelines for preoperative invasive mediastinal staging (IMS) for non-small cell lung cancer (NSCLC), concordance with guidelines and whether the use of these guidelines results in expected frequency of lymph node metastases has not been evaluated. Our objectives were to determine guideline concordance, reasons for nonconcordance, and, in patients who did not receive IMS, to determine the use of operative nodal sampling and final pathologic staging. Methods Patients who had a resection for NSCLC between 2010 and 2012 were identified from the Institutional Cancer Registry. A chart audit was performed to determine adherence to Cancer Care Ontario (CCO) IMS guideline criteria, and pathologic reports were reviewed to determine postresection staging. Results Of 242 resections performed in the study period 102 (42%) did not receive IMS. 66 patients (65%) did not require IMS based on CCO guidelines and thus were concordant with guidelines, whereas 36 (36%) were guideline nonconcordant. Of 102 patients who did not have preoperative IMS, only 72 had intraoperative lymph node assessment and only 35 (34%) had sampling of three or more ipsilateral (N2) nodal stations. In the guideline concordant group, 2 of 66 patients (5%) had positive N2 nodes, whereas in the nonconcordant group 3 of 36 patients (11%) were N2 positive. Conclusions Although overall IMS was used in only 140 patients (58%), concordance with guidelines was high at 85% (206 of 242 patients). However, rates of intraoperative nodal sampling for non-IMS cases (both concordant and nonconcordant) was lower than expected, resulting in potentially understaged patients.

Pulmonary lobectomy is the standard of care for resection of non-small cell lung cancer (NSCLC). Patients with compromised lung function who are considered high risk may be denied surgical treatment; thus, proper identification of those truly at high risk is critical. Video-assisted thoracic surgery (VATS) may reduce the operative risk. This study reviews our institutional experience of pulmonary lobectomy by open thoracotomy or VATS techniques in patients deemed to be high risk.A retrospective review of an institutional database was performed for all patients undergoing lobectomy from 2002 to 2010. Patients were grouped into high-risk (HR) and standard-risk (SR) cohorts according to the American College of Surgeons Oncology Group Z4099/Radiation Therapy Oncology Group 1021 criteria.From 2002 to 2010, 72 HR and 536 SR patients underwent lobectomy. Mean age was 73 years for HR and 66 years for SR (p0.0001). Rates of overall (p 0.0001) and pulmonary complications (p0.0001) were significantly higher in the HR group. However, when HR patients were resected by VATS, there was no significant difference in overall (p = 0.1299) or pulmonary complications (p = 0.2292) compared with the SR VATS group. Moreover, overall survival was significantly lower for HR patients who had an open operation compared with VATS lobectomy or SR open (p = 0.0028).VATS lobectomy offers patients who are considered to be at increased risk for open lobectomy a feasible procedure, with no difference in overall survival compared with SR patients, and decreased morbidity compared with open lobectomy. VATS lobectomy should be considered for patients who historically may not have been considered for surgical resection.

To assess the cost-effectiveness of various modes of mediastinal staging in non-small cell lung cancer (NSCLC) in a single-payer health care system.We performed a decision analysis to compare the health outcomes and costs of 4 mediastinal staging strategies: no invasive staging, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), mediastinoscopy, and EBUS-TBNA followed by mediastinoscopy if EBUS-TBNA is negative. We determined incremental cost effectiveness ratios (ICER) for all strategies and performed comprehensive deterministic sensitivity analyses using a willingness to pay threshold of $80,000/quality adjusted life year (QALY).Under the base-case scenario, the no invasive mediastinal staging strategy was least effective (QALY, 5.80) and least expensive ($11,863), followed by mediastinoscopy, EBUS-TBNA, and EBUS-TBNA followed by mediastinoscopy with 5.86, 5.87, and 5.88 QALYs, respectively. The ICER was ∼$26,000/QALY for EBUS-TBNA staging and ∼$1,400,000/QALY for EBUS-TBNA followed by mediastinoscopy. The mediastinoscopy strategy was dominated. Once pN2 exceeds 2.5%, EBUS-TBNA staging is cost-effective (∼$80,000/QALY). Once the pN2 reaches 57%, EBUS-TBNA followed by mediastinoscopy is cost-effective (ICER ∼$79,000/QALY). Once EBUS-TBNA sensitivity exceeds 25%, EBUS-TBNA staging is cost-effective (ICER ∼$79,000/QALY). Once pN2 exceeds 25%, confirmatory mediastinoscopy should be added, in cases of EBUS-TBNA sensitivity ≤ 60%.Invasive mediastinal staging in NSCLC is unlikely to be cost-effective in clinical N0 patients if pN22.5%. In patients with probability of mediastinal metastasis between 2.5% and 57% EBUS-TBNA is cost-effective as the only staging modality. Confirmatory mediastinoscopy should be considered in high-risk patients (pN2 57%) in case of negative EBUS-TBNA.

Summary Background Ex-vivo lung perfusion (EVLP) can be used to extend overall lung preservation time by splitting one long cold ischaemic time into two shorter ones and interposing an additional EVLP time. We assessed the outcomes after clinical transplantation of lungs with more than 12 h of preservation time. Methods For this retrospective study, we searched the Toronto Lung Transplant Program database for patients who had received at least one lung transplant between Jan 1, 2006, and April 30, 2015, at a single hospital in Toronto, Canada. We split the identified patients into those with a total preservation time of more than 12 h and those with a total preservation time of less than 12 h to act as the control group. Total preservation time was defined as the sum of first cold ischaemic time, EVLP time, and second cold ischaemic time. We excluded patients if they had received a heart–lung transplant or were younger than 18 years. In bilateral lung transplantations, we used the longer preservation time of the two lungs for analysis. Lung preservation was done according to present standards of care and EVLP was done according to the Toronto EVLP technique. The primary outcomes were survival and International Society for Heart and Lung Transplantation Primary Graft Dysfunction (PGD) grade at 72 h post-transplantation. We compared outcomes with our control group using univariable and multivariable models. Findings We identified 906 patients who met eligibility criteria and had sufficient data for analysis ( vs >12 h group [n=97]; 875·7 min [109·0]). Median hospital and intensive-care unit length of stay were similar between the less than 12 h group and the more than 12 h group (hospital stay: 23 days [16–42] vs 25·5 days [17–50·25], p=0·60; intensive-care unit stay: 4 days [2–14] vs 4 days [2–16], p=0·53). PGD grade was also not different between the two groups at 72 h post-transplantation (p=0·85). There was also no difference in survival between the two groups as shown on Kaplan-Meier survival curves (p=0·61). Multivariable survival analysis using Cox's model showed increasing recipient age to be a significant variable affecting survival. Interpretation Extension of graft preservation time beyond 12 h with EVLP does not negatively affect early lung transplantation outcomes. Extension of clinical lung preservation times might allow for more transplantations to be done as a result of improved facilitation and increased flexibility around timing of lung transplantation operations. Funding None.

Background: Although many studies have assessed the diagnostic utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the context of a specific disease, few studies have assessed the overall diagnostic yield, sensitivity, and negative predictive value in patients with isolated mediastinal and hilar lymphadenopathy (IMHL). Objective: We evaluated the performance of EBUS-TBNA for diagnosing IMHL in a population with a high prevalence of concurrent or preexisting non-pulmonary malignancy. Methods: A retrospective chart review of patients who underwent EBUS-TBNA from October 2008 to April 2014 was performed to identify patients with IMHL. Patients with known or suspected primary pulmonary malignancy were excluded. When available, EBUS-TBNA results were cross-referenced with further diagnostic investigation or clinical diagnosis based on follow-up. Results: EBUS-TBNA was used to sample 765 lymph nodes from 350 patients. One hundred and fourteen (33.3%) patients had a concurrent or preexisting non-pulmonary malignancy. The overall yield of EBUS-TBNA for specific diagnosis was 300/350 (86%). The diagnostic yield for sarcoidosis, lymphoproliferative disease, metastatic lymphadenopathy from extrathoracic malignancy, and necrotizing granuloma was 123/149 (83%), 27/33 (82%), 20/25 (80%), and 13/19 (68%), respectively. Amongst 50 patients with non-diagnostic EBUS-TBNA, 25 yielded an insufficient sample and another 25 yielded only benign lymphoid material which was not representative of the underlying pathology. Overall, EBUS-TBNA had a sensitivity of 89%, a diagnostic yield of 86%, and a negative predictive value of 79%. Conclusion: For patients with isolated hilar or mediastinal lymphadenopathy and a high background prevalence of concurrent and preexisting non-pulmonary malignancy, EBUS-TBNA is a reliable first-line diagnostic investigation.

The early and long-term results from surgery for locally advanced T4 non-small cell lung cancer (NSCLC) has significantly improved over the past 20 years. Resection of non-small cell lung cancer (NSCLC) invading the aorta can be safely performed in well-selected patients. In most situations, the aortic adventitia can be resected to obtain adequate margins. However, when the tumor extends into the media, resection and reconstruction of the aorta is required. In these situations, the approach depends on the location of the tumor along the aortic arch or the descending aorta. Extracorporeal membrane oxygenation (ECMO) and thoracic endografts have provided improved technology to facilitate aortic resection. Thoracic endografts are particularly helpful for tumors invading the aortic arch or the spine in combination with the descending aorta.

Purpose Pulmonary endarterectomy (PEA) is a curative surgical option for patients with chronic thromboembolic pulmonary hypertension (CTEPH), a disease resulting from chronic pulmonary thromboembolism. The role of sarcopenia (i.e. low skeletal muscle mass) has been shown to be associated with adverse outcomes in surgical populations, but its significance with PEA remains unknown. We sought to evaluate the association of sarcopenia with measures of CTEPH severity and post-operative hospital outcomes. Methods Retrospective, single cohort study of CTEPH patients who underwent PEA from Jan/2014-Dec/2017. Skeletal muscle mass was quantified using computed tomography thoracic muscle cross sectional area (mCSA) with Slice-O-Matic software. The differences between clinical characteristics, cardiac parameters, post-operative hospital stay and complications were evaluated across mCSA quartiles stratified by sex using one-way ANOVA. Post-operative outcomes were adjusted for age, comorbidities, and Jamieson score with multivariable regression. Results 129 patients (age 58±14 years; 41% males; BMI:31±7 kg•m2) were included. Those with lower muscle mass (Q1) had increased median pulmonary vascular resistance (Q1:929 IQR [703-1440] vs. Q4:624 [483-789] dynes), Charlson Comorbidity Index (Q1:3 IQR [2.0-3.5] vs. Q4:1 [0-3]), lower body mass index (Q1:29 ± 6 vs Q4:34 ± 9 kg•m2), six-minute walk distance (Q1:324 ± 149 vs. Q4:455 ± 135 m), and older age (Q1: 65 ± 11 vs. Q4: 50 ± 15 years), p 0.05 for all comparisons). Conclusion Sarcopenia was associated with increased disease severity measures and longer hospital stay post-PEA. Further study is needed to evaluate the contributing factors for the longer hospital stay in sarcopenic patients, its long-term implications and whether sarcopenia is modifiable with pre- and post-PEA rehabilitation strategies.

BACKGROUND: An important and common cause of pulmonary hypertension (PH) is chronic thromboembolic PH (CTEPH). Many care gaps exist in the evaluation of CTEPH including lack of awareness of the dia...

Pulmonary endarterectomy is the treatment of choice for chronic thromboembolic pulmonary hypertension. This case report outlines the importance of venoarterial extracorporeal membrane oxygenation and plasmapheresis as two important options in the management of heparin-induced thrombocytopenia–positive patients requiring urgent pulmonary endarterectomy.

Lobar lung transplantation (LLTx) from deceased donors is a potential solution for donor-recipient size mismatch for small sized recipients. We reviewed our institutional experience to compare outcomes after LLTx to standard lung transplantation (LTx).We retrospectively reviewed transplants in our institution from January 2000 to December 2017. LLTx early- and long-term outcomes were compared with LTx. Additional analysis of outcomes was performed after dividing the cohort into 2 eras (era 1, 2000-2012; era 2, 2013-2017).Among the entire cohort (1665), 75 were LLTx (4.5%). Compared with LTx, LLTx were more frequently bridged to transplant with extracorporeal life support or mechanical ventilation and were transplanted in a rapidly deteriorating status (respectively, 20% vs 4.4%, P = .001; 22.7% vs 7.9, P .001; and 41.3% vs 26.5%, P = .013). LLTx had longer intensive care unit and hospital lengths of stay (respectively, median 17 vs 4 days, and 45 vs 23, both P .001), and greater 30-day mortality (13.3% vs 4.3%, P = .001) and 90-day mortality (17.3% vs 7.2%, P = .003). In era 2, despite a significantly greater 30-day mortality (10.8% vs 2.8%, P = .026), there was no significant difference in 90-day mortality between LLTx and LTx (13.5% vs 5.1%, P = .070). Overall survival at 1, 3, and 5 years was not significantly different between LLTx and LTx (73.2% vs 84.4%, 56.9% vs 68.4% and 50.4% vs 55.8, P = .088).Although LLTx is a high-risk procedure, both mid- and long-term survival are comparable with LTx in all cohorts in the modern era. LLTx therefore represents a valuable surgical option for small-sized recipients.

Detailed guidelines pertaining to radiological assessment of malignant pleural mesothelioma are currently lacking due to the rarity of the disease, complex morphology, propensity to invade multiple planes simultaneously, and lack of specific recommendations within the radiology community about assessment, reporting, and follow-up. In March 2017, a multidisciplinary meeting of mesothelioma experts was co-sponsored by the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and the Mesothelioma Applied Research Foundation. One of the outcomes of this conference was the foundation of detailed, multidisciplinary consensus imaging and management guidelines. Here, we present the recommendations for radiologic assessment of malignant pleural mesothelioma in the setting of clinical trial enrollment. We discuss optimization of imaging parameters across modalities, standardized reporting, and response assessment within clinical trials.

Background: Given poor survival of patients with malignant pleural mesothelioma (MPM) and extrapleural nodal metastasis, pre-operative mediastinal lymph node (LN) staging has been advocated. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) may be a useful pre-operative adjunct in patients with MPM. This study aims to assess performance of EBUS-TBNA for mediastinal LN staging in MPM. Methods: A retrospective chart review of patients with diagnosis of MPM referred to the mesothelioma program at a tertiary Canadian cancer center between January 1, 2012 and December 31, 2014 who received mediastinal LN staging with EBUS-TBNA. Results: Forty-eight patients were included. Average age was 70 years (range, 48–84 years). Mesothelioma subtypes were as follows: epithelioid 34/48 (70.8%), sarcomatoid 4/48 (8.3%), biphasic 7/48 (14.6%) and other 3/48 (6.3%). Stage distribution was as follows: I 18.8%, II 10.4%, III 47.9%, and IV 22.9%. On average 3.4 LNs were sampled per patient (range, 1–5). The mean short axis of a sampled LN was 6.8±3.8 mm. Rapid on Site Evaluation (ROSE) was available in 75.0% (36/48) of the assessments. Prevalence of N2/N3 disease was 35.4% (17/48). EBUS-TBNA sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy were: 16.7%, 100%, 100%, 68.8%, and 70.6%, respectively. EBUS-TBNA mediastinal LN staging prevented unnecessary surgery in 18.8% (9/48 patients) by detection of N2/N3 disease (8 patients) and metastatic secondary malignancy (1 patient). There were no EBUS-TBNA related complications. Conclusions: EBUS-TBNA mediastinal LN staging may impact significantly management of patients with MPM by detecting mediastinal metastatic disease, therefore, preventing morbidity and mortality of surgical management.

Thoracic surgery has significantly evolved over the past 10 years with the advent of minimal invasive techniques that have changed the postoperative course of patients. The objectives during the postoperative period remain, however, similar and include pain management, early mobilization, and aggressive respiratory physiotherapy. While these concepts may appear trivial, their implementation remains a major challenge.

Background: A significant proportion of organ donors currently test positive for hepatitis C virus (HCV) infection. To date, only a few studies have evaluated the safety of using lungs from these donors for transplantation, and no direct interventions to donor organs have been performed with the aim of preventing HCV transmission via organ transplantation. Methods: We performed a single center prospective non-randomized trial where donor lungs from HCV viremic donors were transplanted into HCV negative (HCV-ve) recipients. Outcomes of study recipients were compared to patients receiving HCV-ve donors. Primary endpoints were survival and HCV status at 6 months after transplantation. Prior to implantation, all donor lungs were treated with ex vivo lung perfusion (EVLP) with (n=11) or without (n=11) ultraviolet C (UVC) perfusate irradiation to reduce HCV RNA levels and infectivity. All patients becoming viremic received 12 weeks of sofosbuvir/velpatasvir (S/V) starting at least 2 weeks after transplantation. Findings: During the 13-month study period, 22 patients were transplanted using viremic HCV donors and 187 with HCV-ve donors. Recipient age, lung disease, urgency status and positive donor-recipient HLA crossmatch were similar between the 2 groups. Post-transplant outcomes such as primary graft dysfunction grades, ICU and hospital length of stay, and survival were similar between the 2 groups. Twenty patients (91%) developed HCV viremia within the first week after transplantation and underwent S/V treatment starting at a median of 21 days after transplantation (range 14-71 days). Donor organ treatment with EVLP+UVC was associated with significantly lower recipient viral loads in blood within the first week after transplantation, and prevention of transmission in 2/11 patients. All infected patients achieved negative HCV PCR within 6 weeks of treatment initiation. Two patients presented with HCV relapse within 3 months after S/V completion requiring retreatment. Interpretation: Early and intermediate-term clinical outcomes using viremic HCV donors were similar to patients receiving HCV-ve donor lungs. Donor organ treatment using UVC perfusate irradiation during EVLP showed a significant impact in decreasing HCV viral loads within the first 7 days after transplantation. Trial Registration Number: The trial was registered at clinicaltrials.gov (NCT03112044). Funding Statement: This study was an investigator-initiated study funded by an operating grant from the Canadian Institutes of Health Research (CIHR). Gilead Sciences provided S/V (Epclusa) for all patients in the study. XVIVO perfusion (Gothenburg, Sweden) provided Steen solution for EVLP Declaration of Interests: Dr. Cypel, Waddell and Keshavjee are co-founders of Perfusix Canada, XOR Labs Toronto, and consultants for Lung Bioengineering (United Therapeutics). Ethics Approval Statement: This study was approved by the Research Ethics Board of University Health Network and subjects provided written informed consent while on the transplant waiting list prior to the offer of HCV+ve donor lungs.

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.

Here we summarize the most recent update of mesothelioma research in basic science presented at the 14th iMig2018 international conference. The symposium of basic science track mainly focused on the drivers of mesothelioma initiation and progression, molecular pathogenesis, and perspectives on potential therapeutic approaches. This review covers several promising fields including strategies efficiently inhibiting YAP/TAZ functions or their critical downstream targets, heparanase inhibitors, RAN depletion, and MIF/CD74 inhibitors that may be developed as novel therapeutic approaches. In addition, targeting mesothelioma stem cells by depleting M2-polarized macrophages in tumor microenvironment or blocking Tnfsf18 (GITRL)-GITR signalling might be translated into therapeutic modalities in mesothelioma treatment.

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%., State of the art and research perspectives on the ICU management of patients with pulmonary hypertension and right heart failure, the timing of transplant referral, and the use of extracorporeal life support http://ow.ly/pISA30mfQk4

Objective Men with metastatic nonseminomatous germ cell tumors (NSGCTs) often present with residual chest tumors after chemotherapy. We examined the pathologic concordance of intrathoracic disease and outcomes based on the worst pathology of disease resected at first thoracic surgery. Methods A retrospective analysis was performed of consecutive patients undergoing thoracic resection for metastatic NSGCT in our institution between 2005 and 2018. Results Eighty-nine patients (all men) were included. The median age was 29 years (interquartile range [IQR], 23-35 years). Primary sites were testis (n = 84; 94.4%) and retroperitoneum (n = 5; 5.6%). Eighty-seven patients received chemotherapy before undergoing surgery. Nineteen patients (21.3%; group 1) had malignancy resected at first surgery (OR1), and the other 70 patients had benign disease at OR1 (78.7%; group 2). Concordant pathology between lungs was 85.2% in group 1 and 91% in group 2, and between lung and mediastinum was 50% in group 1 and 72.7% in group 2. Despite no teratoma at OR1, 3 patients (15.8%) in group 2 had resection of teratoma (n = 2) or malignancy (n = 1) at future surgery. After a mean follow-up of 65.5 months (IQR, 23.1-89.2 months) for group 1 and 47.7 months (IQR, 13.0-75.1 months) for group 2, overall survival was significantly worse for group 1 (68.4% vs 92.9%; P = .03). Conclusions The wide range of pathology resected in patients with intrathoracic NSGCT metastases requires careful decision making regarding treatment. Pathologic concordance between lungs is better than that between lung and mediastinum in patients with intrathoracic NSGCT metastases. Aggressive surgical management should be considered for all residual disease due to the low concordance between sites and the potential for excellent long-term survival even in patients with chemotherapy-refractory disease.

On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM. © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

Background Clinical tumor (T), node, and metastasis staging is based on a qualitative assessment of features defining T descriptors and has been found to be suboptimal for predicting the prognosis of patients with malignant pleural mesothelioma (MPM). Previous work suggests that volumetric computed tomography (VolCT) is prognostic and, if found practical and reproducible, could improve clinical MPM classification. Methods Six North American institutions electronically submitted clinical, pathologic, and imaging data on patients with stages I to IV MPM to an established multicenter database and biostatistical center. Two reference radiologists blinded to clinical data independently reviewed the scans; calculated clinical T, node, and metastasis stage by standard criteria; performed semiautomated tumor volume calculations using commercially available software; and submitted the findings to the biostatistical center. Study end points included the feasibility of a multi-institutional VolCT network, concordance of independent VolCT assessments, and association of VolCT with pathological T classification. Results Of 164 submitted cases, 129 were evaluated by both reference radiologists. Discordant clinical staging of most cases confirmed the inadequacy of current criteria. The overall correlation between VolCT estimates was good (Spearman correlation 0.822), but some were significantly discordant. Root cause analysis of the most discordant estimates identified four common sources of variability. Despite these limitations, median tumor volume estimates were similar within subgroups of cases representing each pathological T descriptor and increased monotonically for each reference radiologist with increasing pathological T status. Conclusions The good correlation between VolCT estimates obtained for most cases reviewed by two independent radiologists and qualitative association of VolCT with pathological T status combine to encourage further study. The identified sources of user error will inform design of a follow-up prospective trial to more formally assess interobserver variability of VolCT and its potential contribution to clinical MPM staging.

Objectives Prognostic models for malignant pleural mesothelioma (MPM) are needed to prevent potentially futile outcomes. We combined MPM plasma biomarkers with validated clinical prognostic indices to determine whether stratification of risk for death in 194 patients with MPM improved. Methods Individuals were recruited from three different centers: a discovery cohort (83 patients with MPM) created by combining patients from two U.S. centers and a separate, independent cohort from Canada (111 patients with MPM). Univariable and multivariable analyses were performed on the initial discovery and independent cohorts separately. In the multivariable analyses, prognostic factors were adjusted for the European Organisation for Research and Treatment of Cancer (EORTC) prognostic index (PI) of mesothelioma. The prognostic significance of adding plasma biomarker data to the PI was determined by using the likelihood ratio test, comparing models with and without the addition of biomarker to the clinical PI. The predictive ability of the biomarker was then assessed formally using Harrell’s C-index by applying the fitted model variables of the discovery cohort to the second, independent cohort, including and not including the biomarker with the PI. Results Higher levels of osteopontin and mesothelin were individually associated with worse prognosis after adjusting for the PI. In the independent cohort, incorporating either plasma osteopontin or mesothelin into the baseline predictive PI model substantively and statistically significantly improved Harrell’s C-statistic. In the final prognostic model, log-osteopontin, EORTC clinical prognostic index, and hemoglobin remained as independently significant predictors and the entire prognostic model improved the optimism-corrected Harrell’s C-index significantly, from 0.718 (0.67–0.77) to 0.801 (0.77–0.84). Conclusions These data suggest a possible role for preoperative plasma biomarkers to improve the prognostic capability of the EORTC PI of MPM.

// Adrian G. Sacher 1, 5 , Lisa W. Le 2 , Humberto Lara-Guerra 3 , Thomas K. Waddell 3 , Shingo Sakashita 4 , Zhuo Chen 1 , Lucia Kim 4 , Tong Zhang 4 , Suzanne Kamel-Reid 4 , Alexandra Salvarrey 1, 3 , Gail Darling 3 , Kazuhiro Yasufuku 3 , Shaf Keshavjee 3 , Marc de Perrot 3 , Frances A. Shepherd 1 , Geoffrey Liu 1 , Ming Sound Tsao 3 , Natasha B. Leighl 1 1 Division of Medical Oncology/Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada 2 Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada 3 Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada 4 Department of Pathology and Laboratory Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada 5 Division of Hematology and Oncology, Columbia University/New York-Presbyterian Hospital, New York, New York, USA Correspondence to: Natasha B. Leighl, e-mail: Natasha.Leighl@uhn.ca Keywords: erlotinib, NSCLC, preoperative window study Received: May 04, 2015 Accepted: March 10, 2016 Published: March 25, 2016 ABSTRACT Background: Erlotinib is highly active in EGFR mutant NSCLC, but may benefit some with wild-type tumors. We examined pre-operative erlotinib in early stage NSCLC to assess response and correlation with potential biomarkers. Results: Twenty-five patients were enrolled; 22 received erlotinib treatment and were evaluable (median follow-up 4.4 years). Histology was predominantly adenocarcinoma although 31% had squamous carcinoma. PET response was observed in 2 patients (9%), both with squamous carcinoma. Most (20/22) had stable disease (RECIST), with frequent minor radiographic regression and histologic findings of fibrosis/necrosis including in squamous histology. Only two had EGFR mutations identified, one with minor radiographic response and the other stable disease after 4 weeks of EGFR TKI. High pre-treatment serum levels of TGF-α correlated with primary resistance to erlotinib ( p = 0.02), whereas high post-treatment soluble EGFR levels correlated with response ( p = 0.03). EGFR, PTEN, cMET and AXL expression did not correlate with tumor response. Methods: Clinical stage IA–IIB NSCLC patients received erlotinib 150 mg daily for 4 weeks followed by resection. Tumor response was assessed using CT, PET and pathological response. Tumor genotype was established using Sequenom Mass ARRAY; EGFR, PTEN, cMET and AXL expression was assessed by immunohistochemistry, circulating markers of EGFR activation (TGF-α, amphiregulin, epiregulin, EGFR ECD) by ELISA and EGFR, MET copy number by FISH. Conclusions: Erlotinib appears to demonstrate activity in EGFR wild-type tumors including squamous carcinoma. Further research is needed to characterize those wild-type patients that may benefit from EGFR TKI and predictive biomarkers including TGF-α, EGFR copy and others.

OBJECTIVES Patients with malignant pleural mesothelioma (MPM) eligible for extrapleural pneumonectomy (EPP) may benefit from induction chemotherapy (CT) as historically described, or from induction-accelerated hemithoracic intensity-modulated radiation therapy (IMRT) as a potential alternative. However, the impact of the type of induction therapy on postoperative morbidity and mortality remains unknown. METHODS We performed a retrospective study including every patient who underwent EPP for MPM in our institution between January 2001 and December 2014. Patients without induction treatment (n = 7) or undergoing both induction CT and IMRT (n = 2) were then excluded. The remaining patients (study group) were divided according to the type of induction treatment in Group 1-CT and Group 2-IMRT. Major complications were defined by complications of Grade 3 or higher according to the National Cancer Institute Common Terminology Criteria for Adverse Events 4.0 guidelines. Red blood cell (RBC) transfusion was analysed as a number of packs, and dichotomized as

Objective To evaluate a new protocol of accelerated hemithoracic intensity-modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP) for patients with resectable malignant pleural mesothelioma (MPM). Methods A total of 25 Gy of radiation was delivered in 5 daily fractions over 1 week to the entire ipsilateral hemithorax with concomitant boost of 5 Gy to volumes at high risk based on computed tomography and positron emission tomography scan findings. EPP was performed at 6 ± 2 days after the end of radiation therapy. Adjuvant chemotherapy was offered to patients with ypN2 disease. Results A total of 62 patients were included between November 2008 and October 2014. One patient died in the hospital 2 months after EPP, for an operative mortality of 1.6%, and 2 died after discharged from the hospital for an overall treatment-related mortality (grade 5 toxicity) of 4.8%. Twenty-four patients (39%) developed grade 3 to 5 (grade 3+) complications. On final pathology, 94% of the patients were stage III or IV, and 52% had ypN2 disease. The median survival for all patients as an intention-to-treat analysis was 36 months. The median overall survival and disease-free survival was 51 and 47 months, respectively, in epithelial subtypes, compared with 10 and 8 months in biphasic subtypes ( P = .001). Ipsilateral chest recurrence occurred in 8 patients. Conclusions Accelerated hemithoracic IMRT followed by EPP has become our preferred approach for resectable MPM. The results have been encouraging in patients with epithelial subtype.

This study was undertaken to characterize the molecular and pathological mechanisms of pulmonary vascular remodeling in a patient who developed chronic lung allograft dysfunction and recurrent pulmonary hypertension (PH) 22 years after undergoing a right single lung transplantation for pulmonary arterial hypertension (PAH). Histopathologic examination of the explanted lungs at the time of retransplantation showed characteristics of diffuse vascular remodeling combined with features of acute and chronic thromboemboli and evidence of bronchiolitis obliterans in the right lung allograft. In contrast, the native left lung demonstrated pulmonary arterial changes in keeping with PAH associated with disseminated pulmonary ossification. Real-time polymerase chain reaction and Western blot—performed on the first lung allograft, the native lung, and the new donor lung—demonstrated increased expression of apoptotic-related gene and protein levels in the lung allograft compared with the native PAH lung and the donor lung. Localization of cell apoptosis determined by triple immunostaining for caspase 3, CD31, and smooth muscle actin was positive in the pulmonary endothelial cells but not the smooth muscle cells of the lung allograft, while no positive staining was detected for cell death in the native PAH lung. The presence of PH in the lung allograft 22 years after transplantation was associated with upregulation of apoptotic markers and evidence of apoptotic endothelial cell death compared with the native lung and donor lung.

Thymectomy is part of the therapeutic armamentarium for myasthenia gravis (MG). During the past 80 years, multiple observational studies have shown that thymectomy can potentially fasten stabilization of the disease, reduce the need for corticosteroids, and in some patients lead to complete remission. The benefit from thymectomy in MG is supported by propensity score analysis. A randomized control trial looking at the role of thymectomy in nonthymomatous MG patients was recently completed, but the results are not yet available. The approach and extent of thymectomy remain a topic of intense discussion, particularly with the development of minimally invasive surgery. Although the presence of extracapsular thymic tissue is frequent and well described, the accessibility of these ectopic thymic foci as well as their function and impact on outcome after surgery have been unclear, leading to divergent views between proponents of a maximal cervicomediastinal thymectomy with en bloc resection of all fatty tissue between the thyroid grand and the diaphragm and those of a less extensive approach. In the future, better definition of the type of thymectomy will be important, particularly if prospective studies and randomized trials are performed to compare different surgical approaches. One possibility would be to reserve the term "extended thymectomy" to resection of the thymus with the anterior mediastinal fat between both pleura, the pericardium and diaphragm. More extensive surgery should be specified when it encompasses sites such as the right and left pericardiophrenic angles, the aortopulmonary window, the aortocaval groove and retroinnominate space, and the perithyroid area.

Thymectomy for myasthenia gravis (MG) has been performed since Alfred Blalock observed in 1936 that a young woman had remission of her myasthenia after a thymectomy for a cystic tumor of the thymus. Over the ensuing 80 years, multiple retrospective series of thymectomy for non-thymomatous MG have been published suggesting the potential benefit of thymectomy in patients with MG. However, the role of thymectomy in non-thymomatous MG remained a topic of controversy due to the absence of a randomized trial.

Cytotoxic CD8+ tumor infiltrating lymphocytes (TILs) can contribute to the benefit of hypofractionated radiation, but programmed cell death pathways (programmed cell death 1 and programmed cell death ligand 1 [PD-1/PD-L1]) may provide a mechanism of tumor immune escape. We therefore reviewed the influence of PD-1/PD-L1 and CD8+ TILs on survival after accelerated hypofractionated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma (MPM).Sixty-nine consecutive patients undergoing the protocol of Surgery for Mesothelioma after Radiation Therapy (SMART) between November 2008 and February 2016 were analyzed for the presence of PD-L1 on tumor cells, PD-1 on inflammatory cells, and CD8+ TILs. Comparison was made with a cohort of patients undergoing extrapleural pneumonectomy after induction chemotherapy (n = 14) and no induction (n = 2) between March 2005 and October 2008. PD-L1 expression on tumor cells ≥1% was considered positive. CD8+ TILs and PD-1 expression were scored as a percentage of positive cells.PD-L1 was negative in 75% of MPM after completion of SMART. CD8+ TILs ranged between 0.24% and 8.47% (median 2%). CD8+ TILs ≥2% was associated with significantly better survival in epithelioid MPM (median survival 3.7 years vs 2.3 years in CD8+ TILs2%; P = .02). PD-L1 positivity was associated with worse survival in biphasic MPM (median survival, 0.4 years vs 1.5 years in biphasic PD-L1 negative tumors; P = .07) after SMART. Multivariate analysis demonstrated that epithelioid MPM, nodal disease, and CD8+ TILs were independent predictors of survival after SMART.The influence of tumor microenvironment on survival differs between epithelioid and nonepithelioid MPM. CD8+ TILs is an independent factor associated with better survival in epithelioid MPM treated with SMART.

Photodynamic therapy (PDT) following lung- sparing extended pleurectomy for malignant pleural mesothelioma (MPM) has been investigated as a potential means to kill residual microscopic cells. High expression levels of folate receptor 1 (FOLR1) have been reported in MPM; therefore, targeting FOLR1 has been considered a novel potential strategy. The present study developed FOLR1-targeting porphyrin-lipid nanoparticles (folate-porphysomes, FP) for the treatment of PDT. Furthermore, inhibition of activated epidermal growth factor (EGFR)-associated survival pathways enhance PDT efficacy. In the present study, these approaches were combined; FP-based PDT was used together with an EGFR-tyrosine kinase inhibitor (EGFR-TKI). The frequency of FOLR1 and EGFR expression in MPM was analyzed using tissue microarrays. Confocal microscopy and a cell viability assay were performed to confirm the specificity of FOLR1-targeting cellular uptake and photocytotoxicity in vitro. In vivo fluorescence activation and therapeutic efficacy were subsequently examined. The effects of EGFR-TKI were also assessed in vitro. The in vivo combined antitumor effect of EGFR-TKI and FP-PDT was then evaluated. The results revealed that FOLR1 and EGFR were expressed in 79 and 89% of MPM samples, respectively. In addition, intracellular uptake of FP corresponded well with FOLR1 expression. When MPM cells were incubated with FP and then irradiated at 671 nm, there was significant in vitro cell death, which was inhibited in the presence of free folic acid, thus suggesting the specificity of FPs. FOLR1 targeting resulted in disassembly of the porphysomes and subsequent fluorescence activation in intrathoracic disseminated MPM tumors, as demonstrated by ex vivo tissue imaging. FP-PDT resulted in significant cellular damage and apoptosis in vivo. Furthermore, the combination of pretreatment with EGFR-TKI and FP-PDT induced a marked improvement of treatment responses. In conclusion, FP-based PDT induced selective destruction of MPM cells based on FOLR1 targeting, and pretreatment with EGFR-TKI further enhanced the therapeutic response.

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)

96 Background: Palliative chemotherapy, the mainstay for incurable eMPM, is offered to patients with good standing performance status (ECOG 0-1). We determined the proportion of eMPM patients experiencing moderate (Mod) to severe (Sev) symptoms while on palliative chemotherapy using ESAS symptom scores at diagnosis and during first and subsequent lines of systemic therapy. Methods: ESAS scores (0=no symptom; 10=worst symptom) were routinely captured in eMPM patients at Princess Margaret (Toronto, Canada). Retrospective chart review collected ESAS, clinical, treatment and outcome data. ESAS scores and proportions were summarized within baseline, firstline, and subsequent lines of therapy. Mod symptom was defined as ESAS scores of 4-6, and Sev as 7-10. ESAS scores between treatment lines were analyzed by Mann-Whitney U tests. Locally weighted smoothing (LOESS) plots assessed ESAS scores over treatment duration. Results: Of 37 palliative eMPM patients, the most frequent baseline symptoms were fatigue (33% Mod, 25% Sev), dyspnea (27% Mod; 17% Sev), anxiety (21% Mod; 21% Sev) and depression (34% Mod; 4% Sev). Overall well-being was poor in 45% of patients (31% Mod; 14% Sev). Compared to baseline, patients on firstline therapy reported increased pain ( p = 0.002), poor appetite ( p = 0.005) and nausea ( p = 0.02); decreased depression ( p = 0.03) and anxiety ( p = 0.006); and stable well-being ( p = 0.27). In patients well enough for subsequent therapy, patients reported reduced drowsiness ( p = 0.01) and improved overall well-being ( p = 0.04) compared to firstline therapy. LOESS plot patterns were similar between firstline and subsequent lines of treatment. Conclusions: eMPM patients had high symptom scores at the time of diagnosis. However, patients’ depression and anxiety decreased when starting initial treatment, and general well-being was stable. Of patients fit enough for subsequent lines of therapy, there were improvements in drowsiness and overall well-being. When selectively used, palliative systemic therapy of all lines are associated with some improved symptoms, but pain, poor appetite, and nausea need to be monitored and managed more effectively.

On March 28- 29, 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation convened the NCI-International Association for the Study of Lung Cancer- Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists, and the U.S. Food and Drug Administration to focus on the development of clinical trials for patients in whom malignant pleural mesothelioma has been diagnosed. In light of the discovery of new cancer targets affecting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least two or three practice-changing multimodality clinical trials to be conducted through NCI's National Clinical Trials Network.

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. 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. 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). 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.

Background Ex vivo lung perfusion (EVLP) is being increasingly applied as a method to evaluate and treat donor lungs for transplantation. However, with the previous limited worldwide experience, no studies have been able to evaluate the impact of indication for EVLP on organ utilization rates and recipient outcomes after lung transplantation (LTx). We examined these outcomes in a large-cohort, single-center series of clinical EVLP cases. Methods All EVLP procedures performed at our institution between October 2008 and December 2017 were examined. The EVLPs were divided into 4 groups based on the indication for the procedure: group 1, high-risk brain death donors (HR-BDD); group 2, standard-risk donation after cardiac death (S-DCD); group 3, high-risk donation after cardiac death (HR-DCD); and group 4, logistics (LOGISTICS, the need for prolongation of preservation time or organ retrieval by a different transplantation team). Results During the study period, a total of 1106 lung transplants were performed in our institution. In this period, 372 EVLPs were performed, 255 (69%) of which were accepted for transplantation, resulting in 262 transplants. Utilization rates were 70% (140 of 198) for group 1, 82% (40 of 49) for group 2, 63% (69 of 109) for group 3, and 81% (13 of 16) for group 4 (P = .42, Fisher's exact test). Recipient age (P = .27) and medical diagnosis (P = .31) were not different across the 4 groups. Kaplan–Meier survival by EVLP indication group demonstrated no differences. Thirty-day mortality was 2.1% in group 1, 5% in group 2, 2.9% in group 3, and 0% in group 4 (P = .87, Fisher's exact test). The median days of mechanical ventilation, intensive care unit stay, and hospital stay were 2, 4, and 21 in group 1; 2, 3, and 21 in group 2; 3, 5, and 28 in group 3; and 2, 4, and 17 in group 4 (P = .29, .17, and .09, respectively, Kruskal–Wallis rank-sum test). Conclusions Clinical implementation of EVLP has allowed our program to expand the annual lung transplantation activity by 70% in this time period. It has improved confidence in the utilization of DCD lungs and BDD lungs, with an average 70% utilization of post-EVLP treated donor lungs with excellent outcomes, while addressing significant challenges in donor lung assessment and the logistics of “real-life” clinical lung transplantation.

OBJECTIVE: To evaluate the diagnostic value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in stereotactic body radiation therapy (SBRT) candidates and compare with computed tomography (CT) and positron emission tomography (PET). METHODS: Inclusion criteria for this single institutional retrospective study were 1) biopsy-proven or suspicious NSCLC with diameter