Publications by authors named "Shaf Keshavjee"

451 Publications

Thymoma pathology and Myasthenia Gravis outcomes.

Muscle Nerve 2021 Mar 6. Epub 2021 Mar 6.

Ellen and Martin Prosserman Centre for Neuromuscular Diseases, University Health Network, Toronto General Hospital, University of Toronto, Toronto, Canada.

Introduction: There is limited evidence regarding the impact of World Health Organisation (WHO) subtype of thymoma on post-thymectomy outcome of thymoma-associated myasthenia gravis (TAMG). The objective was to determine if the pathological subtypes of thymoma were associated with post-thymectomy outcomes of myasthenia gravis (MG), in patients with TAMG.

Methods: We performed a retrospective study of consecutive patients with TAMG who attended the neuromuscular clinic between January 2018 and December 2019 with a minimum follow-up of 1 year after thymectomy. Outcome measures were MG impairment index (MGII), single-simple question (SSQ), Myasthenia Gravis Foundation of America post-intervention status (MGFA PIS) and non-responder MG status at last assessment.

Results: 95 patients were included; mean age at onset was 48.1 ± 12.1 years; 54(56.8%) were females. Thirteen patients developed MG post-thymectomy. The most common thymoma was WHO type B2 in 39(41.1%) Most patients (40, 42.1%) had Masaoka stage II thymoma. There was no association of thymoma subtypes or Masaoka stage of disease with age, gender, MG phenotype, serology, post-thymectomy onset, interval from onset to thymectomy, MGII, SSQ, MGFA PIS or non-responder status. Associations were found between positive serology and lower MGII (11.1 ± 14.2 vs 23 ± 12.9, p = 0.050), thymic follicular hyperplasia (TFH) and higher SSQ (89.3 ± 11.7 vs 80.1 ± 20.2, p-0.043), and lack of recurrence and higher SSQ (84.1 ± 18 vs 72.5 ± 20, p = 0.037).

Discussion: The WHO pathological subtype of thymoma did not correlate with MG outcomes. However, positive acetylcholine antibody serology, presence of TFH and non-recurrence of thymoma, predict a favourable outcome. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/mus.27220DOI Listing
March 2021

Expanding controlled donation after the circulatory determination of death: statement from an international collaborative.

Intensive Care Med 2021 Feb 26. Epub 2021 Feb 26.

Chief Medical Officer, New England Donor Services, 60 1st Ave, Waltham, MA, 02451, USA.

A decision to withdraw life-sustaining treatment (WLST) is derived by a conclusion that further treatment will not enable a patient to survive or will not produce a functional outcome with acceptable quality of life that the patient and the treating team regard as beneficial. Although many hospitalized patients die under such circumstances, controlled donation after the circulatory determination of death (cDCDD) programs have been developed only in a reduced number of countries. This International Collaborative Statement aims at expanding cDCDD in the world to help countries progress towards self-sufficiency in transplantation and offer more patients the opportunity of organ donation. The Statement addresses three fundamental aspects of the cDCDD pathway. First, it describes the process of determining a prognosis that justifies the WLST, a decision that should be prior to and independent of any consideration of organ donation and in which transplant professionals must not participate. Second, the Statement establishes the permanent cessation of circulation to the brain as the standard to determine death by circulatory criteria. Death may be declared after an elapsed observation period of 5 min without circulation to the brain, which confirms that the absence of circulation to the brain is permanent. Finally, the Statement highlights the value of perfusion repair for increasing the success of cDCDD organ transplantation. cDCDD protocols may utilize either in situ or ex situ perfusion consistent with the practice of each country. Methods to accomplish the in situ normothermic reperfusion of organs must preclude the restoration of brain perfusion to not invalidate the determination of death.
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http://dx.doi.org/10.1007/s00134-020-06341-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907666PMC
February 2021

Successful lung transplantation from lungs procured 12 hours after withdrawal of life-sustaining therapy: Changing the paradigm of controlled DCD donors?

J Heart Lung Transplant 2021 Jan 23. Epub 2021 Jan 23.

Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1016/j.healun.2021.01.1389DOI Listing
January 2021

IL-6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndrome.

Clin Transl Immunology 2021 28;10(2):e1243. Epub 2021 Jan 28.

Toronto Lung Transplant Program Toronto General Hospital Toronto ON Canada.

Objective: COPA syndrome is a genetic disorder of retrograde cis-Golgi vesicle transport that leads to upregulation of pro-inflammatory cytokines (mainly IL-1β and IL-6) and the development of interstitial lung disease (ILD). The impact of COPA syndrome on post-lung transplant (LTx) outcome is unknown but potentially detrimental. In this case report, we describe progressive allograft dysfunction following LTx for COPA-ILD. Following the failure of standard immunosuppressive approaches, detailed cytokine analysis was performed with the intention of personalising therapy.

Methods: Multiplexed cytokine analysis was performed on serum and bronchoalveolar lavage (BAL) fluid obtained pre- and post-LTx. Peripheral blood mononuclear cells (PMBCs) obtained pre- and post-LTx were stimulated with PMA, LPS and anti-CD3/CD28 antibodies. Post-LTx endobronchial biopsies underwent microarray-based gene expression analysis. Results were compared to non-COPA LTx recipients and non-LTx healthy controls.

Results: Multiplexed cytokine analysis showed rising type I/II IFNs, and IL-6 in BAL post-LTx that decreased following treatment of acute rejection but rebounded with further clinical deterioration. stimulation of PMBCs suggested that myeloid cells were driving deterioration, through IL-6 signalling pathways. Tocilizumab (IL-6 receptor antibody) administration for 3 months (4 mg kg, monthly) effectively suppressed IL-6 levels in BAL. Mucosal gene expression profile following tocilizumab suggested greater similarity to normal.

Conclusion: Clinical effectiveness of IL-6 receptor blockade was not observed. However, we identified IL-6 upregulation associated with graft injury, effective IL-6 suppression with tocilizumab and evidence of beneficial effect on molecular transcripts. This mechanistic analysis suggests a role for IL-6 blockade in post-LTx care that should be investigated further.
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http://dx.doi.org/10.1002/cti2.1243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843402PMC
January 2021

Safety of continuous 12-hour delivery of antimicrobial doses of inhaled nitric oxide during ex vivo lung perfusion.

J Thorac Cardiovasc Surg 2020 Dec 10. Epub 2020 Dec 10.

Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Introduction: High-dose nitric oxide (NO) has been shown effective against a variety of micro-organisms in vitro, including common bacteria found in donor organs. However, clinical obstacles related to its implementation in vivo are the formation of methemoglobin and the accumulation of toxic nitrogen compounds. Ex vivo lung perfusion (EVLP) is a platform that allows for organ maintenance with an acellular perfusion solution, thus overcoming these limitations. The present study explores the safety of continuous high-dose inhaled (iNO) during EVLP for an extended period of 12 hours.

Methods: Lungs procured from Yorkshire pigs were randomized into control (standard ventilation) and treatment (standard ventilation + 200 ppm iNO) groups, then perfused with an acellular solution for 12 hours (n = 4/group). Lung physiology and biological markers were evaluated.

Results: After 12 hours of either standard EVLP or EVLP + 200 ppm iNO, we did not notice any significant physiologic difference between the groups: pulmonary oxygenation (P = .586), peak airway pressures (P = .998), and dynamic (P = .997) and static (P = .908) lung compliances. In addition, no significant differences were seen among proinflammatory cytokines measured in perfusate and lung tissue. Importantly, most common toxic compounds were kept at safe levels throughout the treatment course.

Conclusions: High-dose inhaled NO delivered continuously over 12 hours appears to be safe without inducing any significant pulmonary inflammation or deterioration in lung function. These findings support further efficacy studies to explore the use of iNO for the treatment of infections in donor lungs during EVLP.
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http://dx.doi.org/10.1016/j.jtcvs.2020.11.150DOI Listing
December 2020

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

Lancet Oncol 2021 02 12;22(2):190-197. Epub 2021 Jan 12.

Princess Margaret Cancer Centre, Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1016/S1470-2045(20)30606-9DOI Listing
February 2021

CYP51A polymorphisms of Aspergillus fumigatus in lung transplant recipients: Prevalence, correlation with phenotype, and impact on outcomes.

Med Mycol 2021 Jan 8. Epub 2021 Jan 8.

Transplant Infectious Diseases, Multi-organ Transplant Program, University Health Network, Toronto, ON, Canada.

Azole resistance in Aspergillus fumigatus is increasing worldwide and can affect prognosis. It is mostly mediated by cytochrome P51 (CYP51) mutations. In lung transplant recipients (LTR), little is known regarding the prevalence and clinical impact of CYP51 mutations. One hundred thirty-one consecutive A. fumigatus isolates from 103 patients were subjected to CYP51A genotyping through PCR and sequencing. Antifungal susceptibility testing was performed using the Sensititre YeastOne YO-9© broth microdilution technique. Correlations between genotype, phenotype, clinical manifestations of Aspergillus infection, and clinical outcomes were made. Thirty-four (26%) isolates harbored mutations of CYP51A; N248K (n = 14) and A9T (n = 12) were the most frequent. Three isolates displayed multiple point mutations. No significant influences of mutational status were identified regarding azole MICs, the clinical presentation of Aspergillus disease, 1-year all-cause mortality, and clinical outcomes of invasive forms. In the specific context of lung transplant recipients, non-hotspot CYP51A-mutated isolates are regularly encountered; this does not result in major clinical consequences or therapeutic challenges.

Lay Summary: In 131 isolates of Aspergillus fumigatus isolates originating from 103 lung transplant recipients, the CYP51A polymorphism rate was 26%, mostly represented by N248K and A9T mutations. These mutations, however, did not significantly impact azoles minimal inhibitory concentrations or clinical outcomes.
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http://dx.doi.org/10.1093/mmy/myaa110DOI Listing
January 2021

Alpha-1 Antitrypsin for COVID-19 Treatment: Dual Role in Antiviral Infection and Anti-Inflammation.

Front Pharmacol 2020 11;11:615398. Epub 2020 Dec 11.

Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.

Many drugs have been approved for clinical trials for the treatment of COVID-19 disease, focusing on either antiviral or anti-inflammatory approaches. Combining antiviral and anti-inflammatory drugs or therapies together may be more effective. Human alpha-1 antitrypsin (A1AT) is a blood circulating glycoprotein that is best known as a protease inhibitor. It has been used to treat emphysema patients with A1AT deficiency for decades. We and others have demonstrated its role in reducing acute lung injury by inhibiting inflammation, cell death, coagulation, and neutrophil elastase activation. Recently, A1AT has been found to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by inhibiting transmembrane serine protease 2 (TMPRSS2), a protease involved in the entry of SARS-CoV-2 into host cells. This dual role of both antiviral infection and anti-inflammation makes A1AT a unique and excellent candidate for COVID-19 treatment. Three clinical trials of A1AT for COVID-19 treatment have recently been approved in several countries. It is important to determine whether A1AT can prevent the progress from moderate to severe lung injury and eventually to be used to treat COVID-19 patients with acute respiratory distress syndrome.
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http://dx.doi.org/10.3389/fphar.2020.615398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759674PMC
December 2020

Donor ventilation parameters as predictors for length of mechanical ventilation after lung transplantation: Results of a prospective multicenter study.

J Heart Lung Transplant 2021 Jan 28;40(1):33-41. Epub 2020 Oct 28.

Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: The evaluation of donor lungs heavily depends on the subjective judgment of the retrieval surgeon. As a consequence, acceptance rates vary significantly among transplant centers. We aimed to determine donor ventilation parameters in a prospective study and test if they could be used as objective quality criteria during organ retrieval.

Methods: A prospective evaluation of lung donors was performed in 3 transplant centers. Ventilation parameters were collected at the time of retrieval using a standardized ventilation protocol. Recipient length of mechanical ventilation (LMV) was defined as the primary end point, and collected data was used to build linear models predicting LMV.

Results: In total, 166 donors were included in this study. Median LMV after transplantation was 32 hours (interquartile range: 20-63 hours). Peak inspiratory pressure and dynamic compliance (C) at the time of retrieval, but not the partial pressure of oxygen/fraction of inspired oxygen (P/F) ratio, correlated with recipient LMV in Spearman correlations (r = 0.280, p = 0.002; r = -0.245, p = 0.003; and r = 0.064, p = 0.432, respectively). Linear models were built to further evaluate the impact of donor ventilation parameters on LMV. The first model was based on donor P/F ratio, donor age, donor intubation time, donor smoking history, donor partial pressure of carbon dioxide, aspiration, chest trauma, and pathologic chest X-ray. This model performed poorly (multiple R-squared = 0.063). In a second model, donor ventilation parameters were included, and C was identified as the strongest predictor for LMV. The third model was extended by recipient factors, which significantly improved the robustness of the model (multiple R-squared = 0.293).

Conclusion: In this prospective evaluation of donor lung parameters, currently used donor quality criteria poorly predicted recipient LMV. Our data suggest that C is a strong donor-bound parameter to predict short-term graft performance; however, recipient factors are similarly relevant.
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http://dx.doi.org/10.1016/j.healun.2020.10.008DOI Listing
January 2021

Ventilation parameters and early graft function in double lung transplantation.

J Heart Lung Transplant 2021 Jan 13;40(1):4-11. Epub 2020 Oct 13.

Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: Currently, the primary graft dysfunction (PGD) score is used to measure allograft function in the early post-lung transplant period. Although PGD grades at later time points (T48 hours and T72 hours) are useful to predict mid- and long-term outcomes, their predictive value is less relevant within the first 24 hours after transplantation. This study aimed to evaluate the capability of PGD grades to predict prolonged mechanical ventilation (MV) and compare it with a model derived from ventilation parameters measured on arrival at the intensive care unit (ICU).

Methods: A retrospective single-center analysis of 422 double lung transplantations (LTxs) was performed. PGD was assessed 2 hours after arrival at ICU, and grades were associated with length of MV (LMV). In addition, peak inspiratory pressure (P), ratio of the arterial partial pressure of oxygen to fraction of inspired oxygen (P/F ratio), and dynamic compliance (cDyn) were collected, and a logistic regression model was created. The predictive capability for prolonged MV was calculated for both (the PGD score and the model). In a second step, the created model was externally validated using a prospective, international multicenter cohort including 102 patients from the lung transplant centers of Vienna, Toronto, and Budapest.

Results: In the retrospective cohort, a high percentage of extubated patients was reported at 24 hours (35.1%), 48 hours (68.0%), and 72 hours (80.3%) after transplantation. At T0 (time point defined as 2 hours after arrival at the ICU), patients with PGD grade 0 had a shorter LMV with a median of 26 hours (interquartile range [IQR]: 16-47 hours) than those with PGD grade 1 (median: 42 hours, IQR: 27-50 hours), PGD grade 2 (median: 37.5 hours, IQR: 15.5-78.5 hours), and PGD grade 3 (median: 46 hours, IQR: 27-86 hours). However, IQRs largely overlapped for all grades, and the value of PGD to predict prolonged MV was poor. A total of 3 ventilation parameters (P, cDyn, and P/F ratio), determined at T0, were chosen on the basis of clinical reasoning. A logistic regression model including these parameters predicted prolonged MV (>72 hours) with an optimism-corrected area under the curve (AUC) of 0.727. In the prospective validation cohort, the model proved to be stable and achieved an AUC of 0.679.

Conclusions: The prediction model reported in this study combines 3 easily obtainable variables. It can be employed immediately after LTx to quantify the risk of prolonged MV, an important early outcome parameter.
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http://dx.doi.org/10.1016/j.healun.2020.10.003DOI Listing
January 2021

Transcriptomic investigation reveals donor specific gene signatures in human lung transplants.

Eur Respir J 2020 Oct 29. Epub 2020 Oct 29.

Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.

Rationale: Transplantation of lungs from donation after circulatory death (DCD) in addition to donation after brain death (DBD) became routine worldwide to address the global organ shortage. The development of ex vivo lung perfusion (EVLP) for donor lung assessment and repair contributed to the increased use of DCD lungs. We hypothesise that better understanding of the differences between lungs from DBD and DCD donors, and between EVLP and directly transplanted (non-EVLP) lungs, will lead to discovery of the injury specific targets for donor lung repair and reconditioning.

Methods: Tissue biopsies from human DBD (n=177) and DCD (n=65) donor lungs assessed with or without EVLP, were collected at the end of cold ischemic time. All samples were processed with microarray assay. Gene expression, network and pathway analyses were performed using R, Ingenuity Pathway Analysis and STRING. Results were validated with protein assay, multiple logistic regression and 10-fold cross validation.

Results: Our analyses showed that lungs from DBD donors have up-regulation of inflammatory cytokines and pathways. In contrast, DCD lungs display a transcriptome signature of pathways associated with cell death, apoptosis and necrosis. Network centrality revealed specific drug targets to rehabilitate the DBD lungs. Moreover, in DBD lungs, TNFR1/2 signalling pathways and macrophage migration inhibitory factor associated pathways were activated in the EVLP group A panel of genes that differentiate the EVLP from non-EVLP group in DBD lungs was identified.

Conclusion: The examination of gene expression profiling indicates that DBD and DCD lungs have distinguishable biological transcriptome signatures.
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http://dx.doi.org/10.1183/13993003.00327-2020DOI Listing
October 2020

Veno-venous ECMO as a platform to evaluate lung lavage and surfactant replacement therapy in an animal model of severe ARDS.

Intensive Care Med Exp 2020 Oct 27;8(1):63. Epub 2020 Oct 27.

Latner Thoracic Surgery Research Laboratories, Toronto, Canada.

Background: There are limited therapeutic options directed at the underlying pathological processes in acute respiratory distress syndrome (ARDS). Experimental therapeutic strategies have targeted the protective systems that become deranged in ARDS such as surfactant. Although results of surfactant replacement therapy (SRT) in ARDS have been mixed, questions remain incompletely answered regarding timing and dosing strategies of surfactant. Furthermore, there are only few truly clinically relevant ARDS models in the literature. The primary aim of our study was to create a clinically relevant, reproducible model of severe ARDS requiring extracorporeal membrane oxygenation (ECMO). Secondly, we sought to use this model as a platform to evaluate a bronchoscopic intervention that involved saline lavage and SRT.

Methods: Yorkshire pigs were tracheostomized and cannulated for veno-venous ECMO support, then subsequently given lung injury using gastric juice via bronchoscopy. Animals were randomized post-injury to either receive bronchoscopic saline lavage combined with SRT and recruitment maneuvers (treatment, n = 5) or recruitment maneuvers alone (control, n = 5) during ECMO.

Results: PaO/FiO after aspiration injury was 62.6 ± 8 mmHg and 60.9 ± 9.6 mmHg in the control and treatment group, respectively (p = 0.95) satisfying criteria for severe ARDS. ECMO reversed the severe hypoxemia. After treatment with saline lavage and SRT during ECMO, lung physiologic and hemodynamic parameters were not significantly different between treatment and controls.

Conclusions: A clinically relevant severe ARDS pig model requiring ECMO was established. Bronchoscopic saline lavage and SRT during ECMO did not provide a significant physiologic benefit compared to controls.
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http://dx.doi.org/10.1186/s40635-020-00352-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591687PMC
October 2020

Rare indications for a lung transplant. A European Society of Thoracic Surgeons survey.

Interact Cardiovasc Thorac Surg 2020 11;31(5):638-643

Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.

Objectives: The European Society of Thoracic Surgeons Lung Transplantation Working Group promoted a survey to evaluate overall survival in a large cohort of patients receiving lung transplants for rare pulmonary diseases.

Methods: We conducted a retrospective multicentre study. The primary end point was overall survival; secondary end points were survival of patients with the most common diagnoses in the context of rare pulmonary diseases and chronic lung allograft dysfunction (CLAD)-free survival. Finally, we analysed risk factors for overall survival and CLAD-free survival.

Results: Clinical records of 674 patients were extracted and collected from 13 lung transplant centres; diagnoses included 46 rare pulmonary diseases. Patients were followed for a median of 3.1 years. The median survival after a lung transplant was 8.5 years. The median CLAD-free survival was 8 years. The multivariable analysis for mortality identified CLAD as a strong negative predictor [hazard ratio (HR) 6.73)], whereas induction therapy was a protective factor (HR 0.68). The multivariable analysis for CLAD occurrence identified induction therapy as a protective factor (HR 0.51). When we stratified patients by CLAD occurrence in a Kaplan-Meier plot, the survival curves diverged significantly (log-rank test: P < 0.001). Patients with rare diseases who received transplants had chronic rejection rates similar to those of the general population who received transplants.

Conclusions: We observed that overall survival and CLAD-free survival were excellent. We support the practice of allocating lungs to patients with rare pulmonary diseases because a lung transplant is both effective and ethically acceptable.
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http://dx.doi.org/10.1093/icvts/ivaa165DOI Listing
November 2020

Effect of Driving Pressure Change During Extracorporeal Membrane Oxygenation in Adults With Acute Respiratory Distress Syndrome: A Randomized Crossover Physiologic Study.

Crit Care Med 2020 Dec;48(12):1771-1778

1Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada. 2Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, ON, Canada. 3Extracorporeal Life Support Program, Toronto General Hospital, University of Toronto, Toronto, ON, Canada. 4Department of Medicine, Division of Respirology, University Health Network and Sinai Health System, Toronto, ON, Canada. 5Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada. 6Department of Medicine, University Health Network and Sinai Health System, Toronto, ON, Canada. 7Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada. 8Keenan Research Center at the Li-Ka-Shing Knowledge Institute of St. Michael´s Hospital, Toronto, ON, Canada. 9Toronto General Hospital Research Institute, Toronto, ON, Canada.

Objectives: Venovenous extracorporeal membrane oxygenation is an effective intervention to improve gas exchange in patients with severe acute respiratory distress syndrome. However, the mortality of patients with severe acute respiratory distress syndrome supported with venovenous extracorporeal membrane oxygenation remains high, and this may be due in part to a lack of standardized mechanical ventilation strategies aimed at further minimizing ventilator-induced lung injury. We tested whether a continuous positive airway pressure ventilation strategy mitigates ventilator-induced lung injury in patients with severe acute respiratory distress syndrome on venovenous extracorporeal membrane oxygenation, compared with current ventilation practice that employs tidal ventilation with limited driving pressure. We used plasma biomarkers as a surrogate outcome for ventilator-induced lung injury.

Design: Randomized crossover physiologic study.

Setting: Single-center ICU.

Patients: Ten patients with severe acute respiratory distress syndrome supported on venovenous extracorporeal membrane oxygenation.

Interventions: The study included four phases. After receiving pressure-controlled ventilation with driving pressure of 10 cm H2O for 1 hour (phase 1), patients were randomly assigned to receive first either pressure-controlled ventilation 20 cm H2O for 2 hours (phase 2) or continuous positive airway pressure for 2 hours (phase 3), and then crossover to the other phase for 2 hours; during phase 4 ventilation settings returned to baseline (pressure-controlled ventilation 10 cm H2O) for 4 hours.

Measurements And Main Results: There was a linear relationship between the change in driving pressure and the plasma concentration of interleukin-6, soluble receptor for advanced glycation end products, interleukin-1ra, tumor necrosis factor alpha, surfactant protein D, and interleukin-10.

Conclusions: Ventilator-induced lung injury may occur in acute respiratory distress syndrome patients on venovenous extracorporeal membrane oxygenation despite the delivery of volume- and pressure-limited mechanical ventilation. Reducing driving pressure to zero may provide more protective mechanical ventilation in acute respiratory distress syndrome patients supported with venovenous extracorporeal membrane oxygenation. However, the risks versus benefits of such an approach need to be confirmed in studies that are designed to test patient centered outcomes.
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http://dx.doi.org/10.1097/CCM.0000000000004637DOI Listing
December 2020

Eosinophils in transbronchial biopsies: a predictor of chronic lung allograft dysfunction and reduced survival after lung transplantation - a retrospective single-center cohort study.

Transpl Int 2021 Jan 16;34(1):62-75. Epub 2020 Nov 16.

Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada.

Long-term outcomes after lung transplantation remain inferior to those of other solid organ groups. The significance of eosinophils detected on transbronchial biopsies (TBBx) after lung transplantation and their relationship to long-term outcomes remain unknown. A retrospective single-center cohort study was performed of patients transplanted between January 01, 2001, and July 31, 2018, who had at least 1 TBBx with evaluable parenchymal tissue. Multivariable Cox proportional hazard models were used to assess the associations between eosinophil detection and: all-cause mortality and Chronic Lung Allograft Dysfunction (CLAD). 8887 TBBx reports from 1440 patients were reviewed for the mention of eosinophils in the pathology report. 112 (7.8%) patients were identified with eosinophils on at least one TBBx. The median (95% CI) survival time for all patients was 8.28 (7.32-9.31) years. Multivariable analysis, adjusted for clinical variables known to affect post-transplant outcomes, showed that the detection of eosinophils was independently associated with an increased risk of death (HR 1.51, 95% CI 1.24-1.85, p < 0.01) and CLAD (HR 1.35, 95% CI 1.07-1.70, P = 0.01). Eosinophils detected in TBBx are associated with an increased risk of CLAD and death. There may be benefit in specifically reporting the presence of eosinophils in TBBx reports and incorporating their presence in clinical decision-making.
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http://dx.doi.org/10.1111/tri.13760DOI Listing
January 2021

Ex vivo lung perfusion for donor lung assessment and repair: a review of translational interspecies models.

Am J Physiol Lung Cell Mol Physiol 2020 12 30;319(6):L932-L940. Epub 2020 Sep 30.

Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada.

For patients with end-stage lung disease, lung transplantation is a lifesaving therapy. Currently however, the number of patients who require a transplant exceeds the number of donor lungs available. One of the contributing factors to this is the conservative mindset of physicians who are concerned about transplanting marginal lungs due to the potential risk of primary graft dysfunction. Ex vivo lung perfusion (EVLP) technology has allowed for the expansion of donor pool of organs by enabling assessment and reconditioning of these marginal grafts before transplant. Ongoing efforts to optimize the therapeutic potential of EVLP are underway. Researchers have adopted the use of different large and small animal models to generate translational preclinical data. This includes the use of rejected human lungs, pig lungs, and rat lungs. In this review, we summarize some of the key current literature studies relevant to each of the major EVLP model platforms and identify the advantages and disadvantages of each platform. The review aims to guide investigators in choosing an appropriate species model to suit their specific goals of study, and ultimately aid in translation of therapy to meet the growing needs of the patient population.
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http://dx.doi.org/10.1152/ajplung.00295.2020DOI Listing
December 2020

Strategies to prolong homeostasis of ex vivo perfused lungs.

J Thorac Cardiovasc Surg 2020 Aug 13. Epub 2020 Aug 13.

Latner Thoracic Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Objectives: Ex vivo lung perfusion provides an innovative method to assess and repair donor lungs. The current Toronto ex vivo lung perfusion protocol can reliably and reproducibly preserve lungs for 12 hours. A longer ex vivo lung perfusion preservation time could enable the application of more advanced repair therapies and the rescue of more donor lungs for lung transplant. Our objective was to achieve stable 24-hour normothermic ex vivo lung perfusion.

Methods: We systematically examined 3 modifications of ex vivo lung perfusion perfusate administration in a large animal 24-hour ex vivo lung perfusion model. Pig lungs were assigned to 4 groups (n = 5 per group): (1) control; (2) continuous replacement of ex vivo lung perfusion perfusate; (3) modified feed, which used a modified solution to maintain perfusate osmolality by adjusting glucose and sodium levels; and (4) total parenteral nutrition, in which we added parenteral nutrition to the perfusate.

Results: Only 1 lung in the control group completed 24-hour ex vivo lung perfusion. However, 24-hour perfusion was achieved in 4 lungs in the continuous replacement group, 3 lungs in the modified feed group, and 4 lungs in the total parenteral nutrition group. The total parenteral nutrition group achieved significantly longer stable perfusion time compared with control (P = .03). Lung function was significantly improved and inflammatory cytokine production was reduced in the continuous replacement and total parenteral nutrition groups compared with control.

Conclusions: Modifications of ex vivo lung perfusion perfusate toward achieving a stable homeostatic state can extend perfusion time for up to 24 hours. Although these modifications allow for prolonged ex vivo lung perfusion, further research will be required to develop stable lung support beyond 24 hours.
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http://dx.doi.org/10.1016/j.jtcvs.2020.07.104DOI Listing
August 2020

Ex-vivo delivery of monoclonal antibody (Rituximab) to treat human donor lungs prior to transplantation.

EBioMedicine 2020 Oct 16;60:102994. Epub 2020 Sep 16.

Ajmera Transplant Center, University Health Network, PMB 11-175, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada. Electronic address:

Background: Ex-vivo lung perfusion (EVLP) is an innovative platform for assessing donor lungs in the pre-transplant window. In this study, we demonstrate an extension of its utility by administering the anti-CD20 monoclonal antibody, Rituximab, during EVLP. We hypothesized that this would lead to targeted depletion of allograft B-cells which may provide significant clinical benefit, including the potential to reduce latent Epstein-Barr virus (EBV) and decrease the incidence of post-transplant lymphoproliferative malignancies.

Methods: Twenty human donor lungs rejected for transplantation were placed on EVLP with (n = 10) or without (n = 10) 500 mg of Rituximab. Safety parameters such as lung physiology and inflammatory cytokines were evaluated. We measured the delivery efficacy through flow cytometry, immunohistochemistry and ELISA. An in-vitro culture assay, in the presence of complement, was further conducted to monitor whether B-cell depletion would occur in Rituximab-perfused samples.

Findings: Rituximab was successfully delivered to human lungs during EVLP as evidenced by flow cytometric binding assays where lung tissue and lymph node biopsies demonstrated occupied CD20 epitopes after perfusion with the antibody. Lymph nodes from Rituximab perfusions demonstrated a 10.9 fold-reduction in CD20+ staining compared to controls (p = 0.0003). In lung tissue, Rituximab resulted in an 8.75 fold-reduction in CD20+ staining relative to controls (p = 0.0002). This decrease in CD20+ binding illustrates the successful delivery and occupation of epitopes after perfusion with the Rituximab. No apparent safety concerns were seen as exhibited by markers associated with acute cell injury (e.g., proinflammatory cytokines), cell death (e.g., TUNEL staining), or pulmonary physiology. In a post-perfusion tissue culture model, the addition of complement (human serum) resulted in evidence of B-cell depletion consistent with what would be expected with posttransplant activation of bound Rituximab.

Interpretation: Our experiments illustrate the potential of EVLP as a platform to deliver monoclonal antibody therapies to treat donor lungs pretransplant with the goal of eliminating a latent virus responsible for considerable morbidity after lung transplantation.

Funding: Supported by the University Health Network Transplant Center.
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http://dx.doi.org/10.1016/j.ebiom.2020.102994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501077PMC
October 2020

The impact of concordance with a lung cancer diagnosis pathway guideline on treatment access in patients with stage IV lung cancer.

J Thorac Dis 2020 Aug;12(8):4327-4337

Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Ontario, Canada.

Background: Timely access to treatment of lung cancer is dependent on efficient and appropriate patient assessment and early referral for diagnostic workup. This study assesses the impact of Cancer Care Ontario (CCO) Lung Cancer Diagnostic Pathway Guideline (LCDPG) concordance on access to treatment of stage IV lung cancer patients referred to the Diagnostic Assessment Program (DAP) at a Canadian tertiary cancer centre.

Methods: This retrospective cohort study includes patients diagnosed with clinical stage IV lung cancer referred to the DAP at a Canadian tertiary cancer centre between November 1, 2015 and May 31, 2017. Referral concordance was determined based on CCO LCDPG. The primary outcome; time to treatment from initial healthcare presentation; was compared between the concordant and discordant referrals.

Results: Two hundred patients were referred for clinical stage IV lung cancer during the study period. Of these referrals, 151 (75.5%) were assessed and referred in concordance with LCDPG. Guideline concordant referrals were associated with reduced time to treatment from first healthcare presentation compared with guideline discordant referrals (55.3 108.8 days, P<0.001). Time to diagnostic procedure (32.2 86.7 days, P<0.001) and decision to treat (38.5 93.8 days, P<0.001) were also reduced with guideline concordance. The most common reason for discordant assessment and referral was delayed or inadequate investigation of symptoms in a high risk patient (32.7% of discordant referrals).

Conclusions: Guideline concordant assessment and referral of stage IV lung cancer patients results in reduced time to diagnosis and treatment. Future research and education should focus on improving factors that delay DAP referral.
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http://dx.doi.org/10.21037/jtd-20-157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475595PMC
August 2020

Molecular T-cell‒mediated rejection in transbronchial and mucosal lung transplant biopsies is associated with future risk of graft loss.

J Heart Lung Transplant 2020 Dec 26;39(12):1327-1337. Epub 2020 Aug 26.

Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Background: We previously developed molecular assessment systems for lung transplant transbronchial biopsies (TBBs) with high surfactant and bronchial mucosal biopsies, identifying T-cell‒mediated rejection (TCMR) on the basis of the expression of rejection-associated transcripts, but the relationship of rejection to graft loss is unknown. This study aimed to develop molecular assessments for TBBs and mucosal biopsies and to establish the impact of molecular TCMR on graft survival.

Methods: We used microarrays and machine learning to assign TCMR scores to an expanded cohort of 457 TBBs (367 high surfactant plus 90 low surfactant) and 314 mucosal biopsies. We tested the score agreement between TBB-TBB, mucosal-mucosal, and TBB-mucosal biopsy pairs in the same patient. We also assessed the association of molecular TCMR scores with graft loss (death or retransplantation) and compared it with the prognostic associations for histology and donor-specific antibodies.

Results: The molecular TCMR scores assigned in all the TBBs performed similarly to those in high-surfactant TBBs, indicating that variation in alveolation in TBBs does not prevent the detection of TCMR. Mucosal biopsy pieces showed less piece-to-piece variation than TBBs. TCMR scores in TBBs agreed with those in mucosal biopsies. In both TBBs and mucosal biopsies, molecular TCMR was associated with graft loss, whereas histologic rejection and donor-specific antibodies were not.

Conclusions: Molecular TCMR can be detected in TBBs regardless of surfactant and in mucosal biopsies, which show less variability in the sampled tissue than TBBs. On the basis of these findings, molecular TCMR appears to be an important predictor of the risk of future graft failure.

Trial Registration: ClinicalTrials.gov NCT02812290.
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http://dx.doi.org/10.1016/j.healun.2020.08.013DOI Listing
December 2020

Cell-free DNA in human ex vivo lung perfusate as a potential biomarker to predict the risk of primary graft dysfunction in lung transplantation.

J Thorac Cardiovasc Surg 2020 Aug 11. Epub 2020 Aug 11.

Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Cell-free DNA (cfDNA), such as mitochondrial DNA (mtDNA) and nuclear DNA (nuDNA), are known to be released from injured cells and as such have been explored as biomarkers for tissue injury in different clinical settings. Ex vivo lung perfusion (EVLP) has been developed as an effective technique for marginal donor lung functional assessment. We hypothesized that the level of cfDNA in EVLP perfusate may reflect tissue injury and thus can be developed as a biomarker to quantify the degree of donor lung injury or predict the development of primary graft dysfunction (PGD) after lung transplantation (LTx).

Methods: The perfusate from 62 donor lungs transplanted at our institution between May 2010 and December 2015 was sampled for cfDNA at 1 and 4 hours of perfusion. Sequences of genes encoding nicotinamide adenine dinucleotide dehydrogenase 1 (NADH-1) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were used to represent mtDNA and nuDNA, respectively. Levels were quantified by real-time polymerase chain reaction and correlated with clinical outcome after LTx.

Results: In our entire cohort, 14 patients developed PGD grade 3 (PGD3) within 72 hours after LTx. The non-PGD group included 48 patients (PGD0-1). Concentrations of mtDNA in the perfusate of the PGD3 group were significantly higher than those in non-PGD group at 1 hour of EVLP (1874 ± 844 vs 1259 ± 885 copies/μL; P = .011). The perfusate of the PGD3 group had significantly higher levels of nuDNA compared with the non-PGD group at both 1 hour (1498 ± 1895 vs 675 ± 391 copies/μL; P = .008) and 4 hours (4521 ± 5810 vs 1764 ± 1494 copies/μL; P = .001). In donation after cardiac death (DCD) cases, mtDNA levels were significantly higher in the PGD3 group compared with the non-PGD group at 1 hour of EVLP (2060 ± 997 vs 1184 ± 782 copies/μL; P = .040), and the levels of nuDNA were significantly higher in the PGD3 group compared with the non-PGD group at both 1 hour (1021 ± 495 vs 606 ± 305 copies/μL; P = .041) and 4 hours (2358 ± 1028 vs 1185 ± 967 copies/μL; P = .006). In donation after brain death (DBD) cases, cfDNA scores did not show a significant difference.

Conclusions: We found that the amount of cfDNA, especially nuDNA, in EVLP perfusate was higher in the severe PGD group (PGD3) compared with the non-PGD group. This proof-of-concept study supports the concept that the analysis of cfDNA levels in EVLP perfusate can help estimate the damage to donor lungs before implantation. Larger studies are needed to validate this concept.
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http://dx.doi.org/10.1016/j.jtcvs.2020.08.008DOI Listing
August 2020

When to consider lung transplantation for COVID-19.

Lancet Respir Med 2020 10 25;8(10):944-946. Epub 2020 Aug 25.

Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto Lung Transplant Program, Toronto, ON M5G 2C4, Canada.

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http://dx.doi.org/10.1016/S2213-2600(20)30393-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447224PMC
October 2020

Surgical Morbidity of Full-Thickness Chest Wall Resection for Breast Cancer: A Retrospective Study of a National Database.

J Surg Res 2021 01 20;257:161-166. Epub 2020 Aug 20.

Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Division of Thoracic Surgery, University Health Network, Toronto, Ontario, Canada.

Background: Full-thickness chest wall resection (FTCWR) is an underused modality for treating locally advanced primary or recurrent breast cancer invading the chest wall, for which little data exist regarding morbidity and mortality. We examined the postoperative complication rates in breast cancer patients undergoing FTCWR using a large multinational surgical outcomes database.

Methods: A retrospective cohort analysis was conducted using the American College of Surgeons National Surgical Quality Improvement Program database. All patients undergoing FTCWR for breast cancer between 2007 and 2016 were identified (n = 137). Primary outcome measures included 30-d postoperative morbidity, composite respiratory complications, and hospital length of stay (LOS). The secondary aim was to compare the postoperative morbidity of FTCWR to those of patients undergoing mastectomy. One-to-one coarsened exact matching was conducted between two groups, which were then compared with respect to morbidity, mortality, reoperations, readmissions, and LOS.

Results: The overall rate of postoperative morbidity was 11.7%. Two patients (1.5%) had respiratory complications requiring intubation. Median hospital LOS was 2 d. In the coarsened exact matching analysis, 122 patients were included in each of the two groups. Comparison of matched cohorts demonstrated an overall morbidity for the FTCWR group of 11.5% compared with 8.2% for the mastectomy group (8.2%) (P = 0.52).

Conclusions: FTCWR for the local treatment of breast cancer can be performed with relatively low morbidity and respiratory complications. This is the largest study looking at postoperative complications for FTCWR in the treatment of breast cancer. Future studies are needed to determine the long-term outcomes of FTCWR in this patient population.
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http://dx.doi.org/10.1016/j.jss.2020.07.061DOI Listing
January 2021

Lung donation after medical assistance in dying at home.

Am J Transplant 2021 01 10;21(1):415-418. Epub 2020 Sep 10.

Department of Surgery, Toronto Lung Transplant Program and Multiorgan Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.

Organ donation after medical assistance in dying (MAID) has only been possible for patients having the MAID procedure performed at a hospital facility due to prohibitive warm ischemic times. Herein, we describe a protocol for lung donation following MAID at home and demonstrate excellent postoperative outcomes. Lung donation following MAID at home is possible and should be considered by transplant programs.
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http://dx.doi.org/10.1111/ajt.16267DOI Listing
January 2021

International Society for Heart and Lung Transplantation consensus statement for the standardization of bronchoalveolar lavage in lung transplantation.

J Heart Lung Transplant 2020 Jul 15. Epub 2020 Jul 15.

Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Bronchoalveolar lavage (BAL) is a key clinical and research tool in lung transplantation (LTx). However, BAL collection and processing are not standardized across LTx centers. This International Society for Heart and Lung Transplantation-supported consensus document on BAL standardization aims to clarify definitions and propose common approaches to improve clinical and research practice standards. The following 9 areas are covered: (1) bronchoscopy procedure and BAL collection, (2) sample handling, (3) sample processing for microbiology, (4) cytology, (5) research, (6) microbiome, (7) sample inventory/tracking, (8) donor bronchoscopy, and (9) pediatric considerations. This consensus document aims to harmonize clinical and research practices for BAL collection and processing in LTx. The overarching goal is to enhance standardization and multicenter collaboration within the international LTx community and enable improvement and development of new BAL-based diagnostics.
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http://dx.doi.org/10.1016/j.healun.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361106PMC
July 2020

Identifying host microRNAs in bronchoalveolar lavage samples from lung transplant recipients infected with Aspergillus.

J Heart Lung Transplant 2020 Jul 25. Epub 2020 Jul 25.

Transplant Infectious Diseases, Ajmera Family Transplant Centre. Electronic address:

Background: MicroRNAs (miRNAs) are small non-coding RNAs of ∼22 nucleotides that play a crucial role in post-transcriptional regulation of gene expression. Dysregulation of miRNA expression has been shown during microbial infections. We sought to identify miRNAs that distinguish invasive aspergillosis (IA) from non-IA in lung transplant recipients (LTRs).

Methods: We used NanoString nCounter Human miRNA, version 3, panel to measure miRNAs in bronchoalveolar lavage (BAL) samples from LTRs with Aspergillus colonization (ASP group) (n = 10), those with Aspergillus colonization and chronic lung allograft dysfunction (CLAD) (ASPCLAD group) (n = 7), those with IA without CLAD (IA group) (n = 10), those who developed IA with CLAD (IACLAD group) (n = 9), and control patients (controls) (n = 9). The miRNA profile was compared using the permutation test of 100,000 trials for each of the comparisons. We used mirDIP to obtain their gene targets and pathDIP to determine the pathway enrichment.

Results: We performed pairwise comparisons between patient groups to identify differentially expressed miRNAs. A total of 5 miRNAs were found to be specific to IA, including 4 (miR-145-5p, miR-424-5p, miR-99b-5p, and miR-4488) that were upregulated and the pair (miR-4454 + miR-7975) that was downregulated in IA group vs controls. The expression change for these miRNAs was specific to patients with IA; they were not significantly differentiated between IACLAD and IA groups. Signaling pathways associated with an immunologic response to IA were found to be significantly enriched.

Conclusions: We report a set of 5 differentially expressed miRNAs in the BAL of LTRs with IA that might help in the development of diagnostic and prognostic tools for IA in LTRs. However, further investigation is needed in a larger cohort to validate the findings.
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http://dx.doi.org/10.1016/j.healun.2020.07.014DOI Listing
July 2020

Impact of donor time to cardiac arrest in lung donation after circulatory death.

J Thorac Cardiovasc Surg 2020 Jun 16. Epub 2020 Jun 16.

Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objective: Acceptance of lungs from donation after circulatory determination of death has been generally restricted to donors who have cardiac arrest within 60 minutes after withdrawal of life-sustaining therapies. We aimed to determine the effect of the interval between withdrawal of life-sustaining therapies to arrest and recipient outcomes. Second, we aimed to compare outcomes between donation after circulatory determination of death transplants and donation after neurologic determination of death transplants.

Methods: A single-center, retrospective review was performed analyzing the clinical outcomes of transplant recipients who received donation after circulatory determination of death lungs and those who received donation after neurologic determination of death lungs. Donation after circulatory determination of death cases were then grouped on the basis of the interval between withdrawal of life-sustaining therapies and asystole: 0 to 19 minutes (rapid), 20 to 59 minutes (intermediate), and more than 60 minutes (long). Recipient outcomes from each of these groups were compared.

Results: A total of 180 cases of donation after circulatory determination of death and 1088 cases of donation after neurologic determination of death were reviewed between 2007 and 2017. There were no significant differences in the 2 groups in terms of age, gender, recipient diagnosis, and type of transplant (bilateral vs single). Ex vivo lung perfusion was used in 118 of 180 (65.6%) donation after circulatory determination of death cases and 149 of 1088 (13.7%) donation after neurologic determination of death cases before transplantation. The median survivals of recipients who received donation after circulatory determination of death lungs versus donation after neurologic determination of death lungs were 8.0 and 6.9 years, respectively. Time between withdrawal of life-sustaining therapies and asystole was available for 148 of 180 donors (82.2%) from the donation after circulatory determination of death group. Mean and median time from withdrawal of life-sustaining therapies to asystole were 28.6 minutes and 16 minutes, respectively. Twenty donors required more than 60 minutes to experience cardiac arrest, with the longest duration being 154 minutes before asystole was recorded. Recipients of donation after circulatory determination of death lungs who had cardiac arrest at 0 to 19 minutes (90 donors), 20 to 59 minutes (38 donors), and more than 60 minutes (20 donors) did not demonstrate any significant differences in terms of short- and long-term survivals, primary graft dysfunction 2 and 3, intensive care unit stay, mechanical ventilation days, or total hospital stay.

Conclusions: Short- and long-term outcomes in recipients who received donation after neurologic determination of death versus donation after circulatory determination of death lungs are similar. Different withdrawals of life-sustaining therapies to arrest intervals were not associated with recipient outcomes. The maximum acceptable duration of this interval has yet to be established.
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http://dx.doi.org/10.1016/j.jtcvs.2020.04.181DOI Listing
June 2020

Retrospective study of the incidence and outcomes from lung cancer in solid organ transplant recipients.

Lung Cancer 2020 09 26;147:214-220. Epub 2020 Jul 26.

University Health Network, University of Toronto, 610 University Avenue Toronto, M5G2M9, Ontario, Canada.

Objective: Organ transplant recipients (OTR) have an increased risk of developing post-transplant malignancies with lung cancer being one of the most common. In this retrospective study, we investigated incidence, use of systemic therapy and outcomes from lung cancer in OTR.

Materials And Methods: Patients diagnosed with lung cancer following a solid organ transplant at the University Health Network, Toronto, ON, CA, from January 1, 1980 to June 30, 2016 were included. Data for the study population, patient characteristics, treatments and outcomes were abstracted from solid OTR databases, our cancer registry and patient charts. Univariate Kaplan-Meier curves estimated median overall survival (OS) by histology, stage and systemic therapy.

Results: Amongst 7944 OTR (heart [N = 765], lung [n = 1668], liver [n = 2238], kidney [n = 3273]), 101 (1.3 %) developed lung cancer which were included in our analyses. Of these, 81 % were non-small cell lung cancer (NSCLC), 11 % small cell lung cancer (SCLC) and 8% neuroendocrine tumor (NET). Median OS (months) was 25 in those that presented with Stage I/II NSCLC (44 %); 25 for Stage III NSCLC (7%); 3 for Stage IV NCLC (31 %); 10 for Limited stage SCLC (6%); 2 for Extensive stage (ES) SCLC (5%). NSCLC patients that received palliative chemotherapy had an OS of 8 months; ES-SCLC patients that received chemotherapy had an OS of 6 months. Of all patients who received platinum doublets (n = 16), 10 (62.5 %) required dose reductions at some point. Five patients experienced febrile neutropenia (31 %); two (12 %) had other toxicities leading to discontinuation.

Conclusion: Patients with stage I/II NSCLC and NET had poorer survival compared to historical norms in non-transplant patients. Patients who had stage III NSCLC or received palliative systemic therapy had survivals at or slightly below historic norms, although numbers were small. Chemotherapy can be administered in selected OTR patients though dose reductions and febrile neutropenia were common.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.020DOI Listing
September 2020

Deceased-donor lobar lung transplant: A successful strategy for small-sized recipients.

J Thorac Cardiovasc Surg 2020 May 23. Epub 2020 May 23.

Toronto Lung Transplant Program, Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objectives: 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).

Methods: 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).

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1016/j.jtcvs.2020.04.166DOI Listing
May 2020

COVID-19 guidance for triage of operations for thoracic malignancies: A consensus statement from Thoracic Surgery Outcomes Research Network.

J Thorac Cardiovasc Surg 2020 Aug 9;160(2):601-605. Epub 2020 Apr 9.

The extraordinary demands of managing the COVID-19 pandemic has disrupted the world's ability to care for patients with thoracic malignancies. As a hospital's COVID-19 population increases and hospital resources are depleted, the ability to provide surgical care is progressively restricted, forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies as the impact of COVID-19 evolves as each hospital.
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http://dx.doi.org/10.1016/j.jtcvs.2020.03.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146695PMC
August 2020