A machine-learning approach to human ex vivo lung perfusion predicts transplantation outcomes and promotes organ utilization.

Ex vivo lung perfusion (EVLP) is a data-intensive platform used for the assessment of isolated lungs outside the body for transplantation; however, the integration of artificial intelligence to rapidly interpret the large constellation of clinical data generated during ex vivo assessment remains an unmet need. We developed a machine-learning model, termed InsighTx, to predict post-transplant outcomes using n = 725 EVLP cases. InsighTx model AUROC (area under the receiver operating characteristic curve) was 79 ± 3%, 75 ± 4%, and 85 ± 3% in training and independent test datasets, respectively. Excellent performance was observed in predicting unsuitable lungs for transplantation (AUROC: 90 ± 4%) and transplants with good outcomes (AUROC: 80 ± 4%). In a retrospective and blinded implementation study by EVLP specialists at our institution, InsighTx increased the likelihood of transplanting suitable donor lungs [odds ratio=13; 95% CI:4-45] and decreased the likelihood of transplanting unsuitable donor lungs [odds ratio=0.4; 95%CI:0.16-0.98]. Herein, we provide strong rationale for the adoption of machine-learning algorithms to optimize EVLP assessments and show that InsighTx could potentially lead to a safe increase in transplantation rates.

Impact of sex on outcome after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

BACKGROUND: The impact of sex on long-term outcomes after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (PH) remains unclear. We therefore examined the early and long-term outcome after PEA to determine whether sex had an impact on the risk of residual PH and need for targeted PH medical therapy. METHODS: Retrospective study of 401 consecutive patients undergoing PEA at our institution between August 2005 and March 2020 was performed. Primary outcome was the need for targeted PH medical therapy postoperatively. Secondary outcomes included survival and measures of hemodynamic improvement. RESULTS: Females (N = 203, 51%) were more likely to have preoperative home oxygen therapy (29.6% vs 11.6%, p < 0.01), and to present with segmental and subsegmental disease compared to males (49.2% vs 21.2%, p < 0.01). Despite similar preoperative values, females had higher postoperative pulmonary vascular resistance (final total pulmonary vascular resistance after PEA, 437 Dynes∙s∙cm-5 vs 324 Dynes∙s∙cm-5 in males, p < 0.01). Although survival at 10 years was not significantly different between sexes (73% in females vs 84% in males, p = 0.08), freedom from targeted PH medical therapy was lower in females (72.9% vs 89.9% in males at 5 years, p < 0.001). Female sex remained an independent factor affecting the need for targeted PH medical therapy after PEA in multivariate analysis (HR 2.03, 95%CI 1.03-3.98, p = 0.04). CONCLUSIONS: Although outcomes are excellent for both sexes, females had greater need for targeted PH medical therapy in the long-term. Early reassessment and long-term follow-up of these patients are important. Further investigations into possible mechanisms to explain the differences are warranted.

Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer: The ACCELERATE Nonrandomized Clinical Trial.

Importance: Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear. Objective: To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment. Design, Setting, and Participants: This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis. Interventions: Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care. Main Outcome and Measures: The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis. Results: Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P < .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P < .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing. Conclusions and Relevance: This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing. Trial Registration: ClinicalTrials.gov Identifier: NCT04863924.

Rapid Prototyping Techniques for the Development of a Take-Home Surgical Anastomosis Simulation Model.

OBJECTIVE: The objective of this paper is to describe the techniques and process of developing and testing a take-home surgical anastomosis simulation model. DESIGN: Through an iterative process, a simulation model was customized and designed to target specific skill development and performance objectives that focused on anastomotic techniques in thoracic surgery and consist of 3D printed and silicone molded components. Various manufacturing techniques such as silicone dip spin coating and injection molding have been described in this paper and explored as part of the research and development process. The final prototype is a low-cost, take-home model with reusable and replaceable components. SETTING: The study took place at a single-center quaternary care university-affiliated hospital. PARTICIPANTS: The participants included in the model testing were 10 senior thoracic surgery trainees who completed an in-person training session held during an annual hands- on thoracic surgery simulation course. Feedback was then collected in the form of an evaluation of the model from participants. RESULTS: All 10 participants had an opportunity to test the model and complete at least 1 pulmonary artery and bronchial anastomosis. The overall experience was rated highly, with minor feedback provided regarding the set- up and fidelity of the materials used for the anastomoses. Overall, the trainees agreed that the model was suitable for teaching advanced anastomotic techniques and expressed an interest in being able to use this model to practice skill development. CONCLUSIONS: Developed simulation model can be easily reduced, with customized components that accurately simulate real-life vascular and bronchial components suitable for training of anastomoses technique amongst senior thoracic surgery trainees.

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

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

Ex vivo lung evaluation of single donor lungs when the contralateral lung is rejected increases safe use.

OBJECTIVE: The decision to perform a single-lung transplant (SLT) when the contralateral donor lung is rejected is a challenging scenario. The introduction of ex vivo lung perfusion (EVLP) has improved donor lung assessment, and we hypothesize that it has improved SLT outcomes in this setting. METHODS: A retrospective single-center review of all SLTs performed between 2000 and 2017 was performed in which the years 2000 to 2008 were considered the "pre-EVLP era" and 2009 to 2017 the "EVLP era." Recipients of SLT lungs when the contralateral lung was declined were classified into 3 groups: (1) Pre-EVLP era, (2a) EVLP era but EVLP not used, and (2b) EVLP era and EVLP used. The outcomes of interest were survival, time-to-extubation, and intensive care unit and hospital stay. RESULTS: Among 1692 transplants between 2000 and 2017, 244 (14%) were SLT. SLT rate was similar between eras (pre-EVLP 16% vs EVLP 15%), but more SLTs were performed where the contralateral lung was declined in the EVLP era (pre-EVLP 32% vs EVLP 45%, P = .04). Lungs evaluated on EVLP had lower procurement partial pressure of oxygen and were more often from donation after cardiac death donors. Recipients were generally also sicker, with a greater proportion of rapidly deteriorating recipients. Despite this, outcomes were similar between eras with a trend towards lower 30-day mortality in the EVLP era. CONCLUSIONS: The availability of EVLP allowed for better evaluation of marginal single lungs when the contralateral was declined. This has led to increased use rates with preserved outcomes despite use of more extended criteria organs.

Outcomes of lung transplantation from donors with a history of substance abuse.

OBJECTIVE: The study objective was to determine whether donor substance abuse (opioid overdose death, opioid use, cigarette or marijuana smoking) impacts lung acceptance and recipient outcomes. METHODS: Donor offers to a single center from 2013 to 2019 were reviewed to determine if lung acceptance rates and recipient outcomes were affected by donor substance abuse. RESULTS: There were 3515 donor offers over the study period. A total of 154 offers (4.4%) were opioid use and 117 (3.3%) were opioid overdose deaths. A total of 1744 donors (65.0%) smoked cigarettes and 69 donors (2.6%) smoked marijuana. Of smokers, 601 (35.0%) had less than 20 pack-year history and 1117 (65.0%) had more than 20 pack-year history. Substance abuse donors were younger (51.5 vs 55.2 P < .001), more often male (65.6 vs 54.8%, P < .001), more often White (86.2 vs 68.7%, P < .001), and had hepatitis C (8.3 vs 0.8%, P < .001). Donor acceptance was significantly associated with brain dead donors (odds ratio, 1.56, P < .001), donor smoking history (odds ratio, 0.56, P < .001), hepatitis C (odds ratio, 0.35, P < .001), younger age (odds ratio, 0.98, P < .001), male gender (odds ratio, 0.74, P = .004), and any substance abuse history (odds ratio, 0.50, P < .001), but not opioid use, opioid overdose death, or marijuana use. Recipient survival was equivalent when using lungs from donors who had opioid overdose death, who smoked marijuana, or who smoked cigarettes for less than 20 patient-years or more than 20 patient-years, and significantly longer in recipients of opioid use lungs. There was no significant difference in time to chronic lung allograft dysfunction for recipients who received lungs from opioid overdose death or with a history of opioid use, marijuana smoking, or cigarette smoking. CONCLUSIONS: Donor acceptance was impacted by cigarette smoking but not opioid use, opioid overdose death, or marijuana use. Graft outcomes and recipient survival were similar for recipients of lungs from donors who abused substances.

Plasma-first: accelerating lung cancer diagnosis and molecular profiling through liquid biopsy.

Introduction: Molecular profiling of tumor tissue is the gold standard for treatment decision-making in advanced non-small cell lung cancer (NSCLC). Results may be delayed or unavailable due to insufficient tissue, prolonged wait times for biopsy, pathology assessment and testing. We piloted the use of plasma testing in the initial diagnostic workup for patients with suspected advanced lung cancer. Methods: Patients with ⩽15 pack-year smoking history and suspected advanced lung cancer referred to the lung cancer rapid diagnostic program underwent plasma circulating-tumor DNA testing using a DNA-based mutation panel. Tissue testing was performed per standard of care, including comprehensive next-generation sequencing (NGS). The primary endpoint was time from diagnostic program referral to cancer treatment in stage IV NSCLC patients (Cohort A) compared to a contemporary cohort not enrolled in the study (Cohort B) and an historical pre-COVID cohort referred to the program between 2018 and 2019 (Cohort C). Results: From January to June 2021, 20 patients were enrolled in Cohort A; median age was 70.5 years (range 33-87), 70% were female, 55% Caucasian, 85% never smokers, and 75% were diagnosed with NSCLC. Seven had actionable alterations detected in plasma or tissue (4/7 concordant). Fusions, not tested in plasma, were identified by immunohistochemistry for three patients. Mean result turnaround time was 17.8 days for plasma NGS and 23.6 days for tissue (p = 0.10). Mean time from referral to treatment initiation was significantly shorter in cohort A at 32.6 days (SD 13.1) versus 62.2 days (SD 31.2) in cohort B and 61.5 days (SD 29.1) in cohort C, both p < 0.0001. Conclusion: Liquid biopsy in the initial diagnostic workup of patients with suspected advanced NSCLC can lead to faster molecular results and shorten time to treatment even with smaller DNA panels. An expansion study using comprehensive NGS plasma testing with faster turnaround time is ongoing (NCT04862924).

Diversity in National Society Leadership and Podium Speakers in Cardiothoracic Surgery.

BACKGROUND: Women and people of color are often underrepresented in medicine. This study examined the inclusivity and diversity of the recent history of the Canadian Association of Thoracic Surgeons (CATS) in both its executive committees and invited participation at its annual meeting. METHODS: CATS internal records and previous programs of CATS annual meetings were reviewed from 1997 to 2020. Leadership positions, invited speakers, and award recipients were categorized by sex and race. RESULTS: Of 199 CATS members in 2020, 93 (47%) were White men, 64 (32%) were men of color, 24 (12%) were White women, and 18 (9%) were women of color. The majority of CATS presidents (86%), committee chairs (57%), named lecturers (88%), other invited speakers (67%), and major award winners (90%) were White men. Women and people of color were underrepresented. The Resident Research Award was the most diverse: of 23 awards, 10 (44%) have been to men of color, 6 (26%) to White men, 4 (15%) to women of color, and 2 (8%) to White women. CONCLUSIONS: There is a need for more representation and inclusion of both women and people of color at multiple levels in CATS. This includes opportunities for improvement in the make-up of its executive committees, the speakers at its annual conference, and the recipients of its awards. CATS has established an Equity, Diversity and Inclusion Task Force to address this critical issue.

Maintaining technical proficiency in senior surgical fellows during the COVID-19 pandemic through virtual teaching.

BACKGROUND: The novel coronavirus (COVID-19) pandemic has resulted in a severe reduction in operative opportunities for trainees. We hypothesized that augmenting independent practice with a bench model of vascular anastomoses using regular videoconferences and individual feedback would provide a meaningful benefit in the maintenance of technical skills in senior lung transplant surgical fellows. METHODS: A lung transplantation virtual technical skills course was developed, and surgical fellows were provided with a bench model and surgical instruments. Using a virtual communication platform, teaching sessions were held twice weekly, and fellows performed an anastomosis on camera. Video recordings were reviewed and critiqued by attending staff. At the end of the 3-month course, participants were surveyed about their experience. Warm ischemic time was compared between the fellows' 5 most recent cases before and after the pandemic. RESULTS: Seven senior surgical fellows participated and provided feedback. The fellows had graduated medical school an average of 14 years before fellowship, and spent an average of 5 hours (range, 1.3-15 hours) of home practice. Five of the 7 participants (71%) reported improvement in their technical skills and increased confidence in performing lung transplantation. No significant difference in average warm ischemic time in procedures performed by fellows was identified (70.3 minutes prepandemic vs 68.3 minutes postpandemic; P = .68). CONCLUSIONS: A program of virtual technical skills teaching, individual video coaching, and independent practice has provided a benefit in maintaining technical skills in lung transplant surgical fellows during the COVID-19 pandemic, when equivalent operative experience was unavailable. Lessons learned from this exceptional time can be used to create simulation curricula for senior trainees.

Pathologic concordance of resected metastatic nonseminomatous germ cell tumors in the chest.

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.

The Role of Extrapleural Pneumonectomy in Malignant Pleural Mesothelioma.

Extrapleural pneumonectomy (EPP) is the most extensive form of surgery for mesothelioma, involving en bloc resection of visceral and parietal pleura, lung, diaphragm and pericardium, with reconstruction of the pericardium and diaphragm. It can be performed safely in carefully selected patients. It should be performed in experienced centers as part of a multimodality treatment plan. The SMART approach, with a short course of induction hemithoracic radiation followed by EPP has demonstrated safety and value of hypofractionated hemithoracic radiation combined with complete macroscopic resection. We are conducting a clinical trial with oligofractionated hemithoracic radiation in early-stage mesothelioma.

Lung transplantation for cystic fibrosis.

BACKGROUND: The contribution of lung transplantation to the treatment of patients with end-stage cystic fibrosis (CF) has been debated. We aimed to describe achievable outcomes from high-volume CF and lung transplant programs. This study reports on the largest single-center experience of lung transplantation for adult and pediatric patients with CF. It also highlights the evolution of practice and outcomes over time. METHODS: A retrospective analysis of the prospectively collected Toronto Lung Transplant database was carried out. Post-transplant survival in CF was calculated using the Kaplan-Meier method and analyzed with log-rank tests. RESULTS: From 1983 to 2016, a total of 1,885 transplants were performed at our institution, where 364 (19.3%) were CF recipients and another 39 (2.1%) were CF retransplants. The mean age at first transplant was 29.5 ± 9.7 years where 56.6% were males and 91.5% were adults. Pre-transplantation, 88 patients (24.2%) were Burkholderia cepacia complex (BCC)-positive, 143 (39.3%) had diabetes mellitus, and the mean forced expiratory volume in one second was 26.0 ± 7.2%, as predicted at listing. The 1-, 5-, and 10-year probabilities of survival in adults who were BCC-negative were 94%, 70%, and 53%, respectively. Pediatric, BCC-positive, and retransplant recipients had worse survival than adult patients who were BCC-negative. Strategies to improve the donor pool did not affect survival but possibly reduced waitlist mortality. For the entire cohort, the most common causes of death after lung transplant were infection and chronic lung allograft dysfunction. CONCLUSIONS: Lung transplantation for CF provides excellent short- and long-term outcomes. These results strongly support lung transplantation as the standard of care for patients with CF having advanced lung disease.

High Risk for Thoracotomy but not Thoracoscopic Lobectomy.

BACKGROUND: 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. METHODS: 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. RESULTS: From 2002 to 2010, 72 HR and 536 SR patients underwent lobectomy. Mean age was 73 years for HR and 66 years for SR (p < 0.0001). Rates of overall (p < 0.0001) and pulmonary complications (p < 0.0001) 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). CONCLUSIONS: 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.

CT-guided microcoil VATS resection of lung nodules: a single-centre experience and review of the literature.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) is standard of care for small lung resections at many centres. Computed tomography (CT)-guided insertion of microcoils can aid surgeons in performing VATS resections for non-palpable lung nodules deep to the lung surface. METHODS: Retrospective analysis of CT-guided microcoil insertions prior to VATS lung resection at a single institution from October 2008 to January 2014. RESULTS: A total of 63 patients were included (37% male, mean age 61.6±11.4 years). Forty-two patients (67%) had a history of smoking, with 10 current smokers. Sixty one (97%) patients underwent wedge resection and 3 (5%) patients had segmentectomy. Three (5%) patients required intra-operative staple line re-resection for positive or close margins. Eleven (17%) patients had a completion lobectomy, 5 of which were during the same anaesthetic. The average time between the CT-guided insertion and start of operation was 136.6±89.0 min, and average operative time was 84.0±53.3 min. The intra-operative complication rate was 5% (n=3), including 1 episode of hemoptysis, and 2 conversions to thoracotomy. The post-operative complication rate was 8% (5 patients), and included 2 air leaks, 1 hemothorax (drop in hemoglobin), 1 post chest tube removal pneumothorax, and one venous infarction of the lingula after lingula-sparing lobectomy requiring completion lobectomy. . Average post-operative length of stay was 2.2 days. A diagnosis was made for all patients. CONCLUSIONS: CT-guided microcoil insertion followed by VATS lobectomy is safe, with short operative times, short length of stay and 100% diagnosis of small pulmonary nodules. This technique will become more important in the future with increasing numbers of small nodules detected on CT as part of lung cancer screening programs.