Use of a novel donor lung scoring system as a tool for increasing lung recovery for transplantation.

OBJECTIVE: There is a critical shortage of donor lungs for transplantation. We previously developed a parsimonious, highly discriminatory nine-variable Lung Donor (LUNDON) acceptability score. We assess the utility of this score as a tool to improve lung recovery rates for transplantation. METHODS: We examined all brain-dead donors between 2014-2020 from three US organ procurement organizations and validated the score's predictive performance. We examined the trajectory of donors with low (<40) and high (>60) initial LUNDON scores, their corresponding lung recovery rates, factors contributing to score improvement using multivariable regression models, and one-year post-transplant recipient survival. RESULTS: Overall lung recovery was 32.4% (1410/4351). Validation of the LUNDON score in our cohort revealed a C statistic of 0.904 but required intercept calibration. Low initial LUNDON donors that improved to a high final score had an increase in lung recovery rate from 29.3% (1100/3765) to 86.8% (441/508), associated with lower BMI, management in specialized donor care facilities (SDCF), and more bronchoscopies. Donors with high initial and final LUNDON scores had lung recovery rate of 85.2% (98/115), associated with shorter lengths of stay. One-year survival was similar between recipients of low-to-high versus high-to-high LUNDON score donors (0.89 vs 0.84, p=0.2). CONCLUSIONS: The LUNDON score performs well as a predictor of lung recovery in a contemporary cohort but may require OPO-specific calibration. SDCF use, more bronchoscopies, and expediting time from brain death to organ procurement may improve lung utilization. The LUNDON score can be used to guide donor management to expand the donor pool.

Factors associated with incomplete resection for large, locally invasive non-small cell lung cancer.

Background: Large, node-negative but locally invasive non-small cell lung cancer (NSCLC) is associated with increased perioperative risk but improved survival if a complete resection is obtained. Factors associated with positive margins in this population are not well-studied. Methods: We performed a retrospective cohort study using National Cancer Database (NCDB) for adult patients with >5 cm, clinically node-negative NSCLC with evidence of invasion of nearby structures [2006-2015]. Patients were classified as having major structure involvement (azygous vein, pulmonary artery/vein, vena cava, carina/trachea, esophagus, recurrent laryngeal/vagus nerve, heart, aorta, vertebrae) or chest wall invasion (rib pleura, chest wall, diaphragm). Our primary outcome was to evaluate factors associated with incomplete resection (microscopic: R1, macroscopic: R2). Kaplan-Meier analysis and cox multivariable regression models were used to evaluate overall survival (OS), 90-day mortality, and factors associated with positive margins. Results: Among 2,368 patients identified, the median follow-up was 33.8 months [interquartile range (IQR), 12.6-66.5 months]. Most patients were white (86.9%) with squamous cell histology (47.3%). Major structures were involved in 26.4% of patients and chest wall invasion was seen in 73.6%. Four hundred and seventy-eight patients (20.2%) had an incomplete resection. Multivariable analysis revealed that black race [hazard ratio (HR) 1.568, 95% confidence interval (CI): 1.109-2.218] and major structure involvement (HR 1.412, 95% CI: 1.091-1.827) was associated with increased risk of incomplete resection and surgery at an academic hospitals (HR 0.773, 95% CI: 0.607-0.984), adenocarcinoma histology (HR 0.672, 95% CI: 0.514-0.878), and neoadjuvant chemotherapy (HR 0.431, 95% CI: 0.316-0.587) were associated with decreased risk of incomplete resection. The 5-year OS was 43.7% in the entire cohort and 28.8% in patients with positive margins and 47.5% in patients with an R0 resection. Positive margin was also associated with a significantly higher 90-day mortality rate (9.9% versus 6.7%). Conclusions: For patients with large, node-negative NSCLC invading nearby structures, R0 resection portends better survival. Treatment at academic centers, adenocarcinoma histology, and receipt of neoadjuvant chemotherapy are associated with R0 resection in this high-risk cohort.

Validation of a novel donor lung scoring system based on the updated lung Composite Allocation Score.

Lung transplantation (LTx) continues to have lower rates of long-term graft survival compared with other organs. Additionally, lung utilization rates from brain-dead donors remain substantially lower compared with other solid organs, despite a growing need for LTx and the significant risk of waitlist mortality. This study aims to examine the effects of using a combination of the recently described novel lung donor (LUNDON) acceptability score and the newly adopted recipient lung Composite Allocation Score (CAS) to guide transplantation. We performed a review of nearly 18 000 adult primary lung transplants from 2015-2022 across the US with retroactive calculations of the CAS value. The medium-CAS group (29.6-34.5) had superior 1-year posttransplant survival. Importantly, the combination of high-CAS (> 34.5) recipients with low LUNDON score (≤ 40) donors had the worst survival at 1 year compared with any other combination. Additionally, we constructed a model that predicts 1-year and 3-year survival using the LUNDON acceptability score and CAS values. These results suggest that caution should be exercised when using marginally acceptable donor lungs in high-priority recipients. The use of the LUNDON score with CAS value can potentially guide clinical decision-making for optimal donor-recipient matches for LTx.

Utilizing computed tomography volumetry for size matching prior to lung transplantation: a case series.

Background: Appropriate size matching between donor and recipient is critical for successful pulmonary transplantation. Although surrogate measurements such as height and gender are often utilized to approximate predicted lung volume, these methods provide only a gross estimation with wide variability and poor predictive value. Case Description: A single center exploratory study was conducted in which four patients underwent lung transplantation (LT) with pre-operative computed tomography (CT) volumetry obtained in both the donor and recipient to facilitate decision making regarding organ size and suitability. In four cases in which CT volumetry was used, the lung volumes calculated using surrogate measurements significantly overestimated both donor and recipient lung volumes quantified by CT volumetric analysis. All recipients underwent successful LT without necessary graft downsizing. Conclusions: This is an initial report of prospectively utilizing CT volumetry as an adjunct to decision-making regarding suitability of donor lungs. In these cases, CT volumetry facilitated the confident acceptance of donor lungs that were initially predicted to be oversized based on other clinical measures.

Characteristics of donor lungs declined on site and impact of lung allocation policy change.

OBJECTIVE: National and institutional data suggest an increase in organ discard rate (donor lungs procured but not implanted) after a new lung allocation policy was introduced in 2017. However, this measure does not include on-site decline rate (donor lungs declined intraoperatively). The objective of this study is to examine the impact of the allocation policy change on on-site decline. METHODS: We used a Washington University (WU) and our local organ procurement organization (Mid-America Transplant [MTS]) database to abstract data on all accepted lung offers from 2014 to 2021. An on-site decline was defined as an event in which the procuring team declined the organs intraoperatively, and the lungs were not procured. Logistic regression models were used to investigate potentially modifiable reasons for decline. RESULTS: The overall study cohort comprised 876 accepted lung offers, of which 471 donors were at MTS with WU or others as the accepting center and 405 at other organ procurement organizations with WU as the accepting center. At MTS, the on-site decline rate increased from 4.6% to 10.8% (P = .01) after the policy change. Given the greater likelihood of non-local organ placement and longer travel distance after policy change, the estimated cost of each on-site decline increased from $5727 to $9700. In the overall group, latest partial pressure of oxygen (odds ratio [OR], 0.993; 95% confidence interval [CI], 0.989-0.997), chest trauma (OR, 2.474; CI, 1.018-6.010), chest radiograph abnormality (OR, 2.902; CI, 1.289-6.532), and bronchoscopy abnormality (OR, 3.654; CI, 1.813-7.365) were associated with on-site decline, although lung allocation policy era was unassociated (P = .22). CONCLUSIONS: We found that nearly 8% of accepted lungs are declined on site. Several donor factors were associated with on-site decline, although lung allocation policy change did not have a consistent impact on on-site decline.

Pulmonary Carcinoid Tumorlet in the Explanted Lungs for Lung Transplantation: A Case Series of 15 Patients.

BACKGROUND: Pulmonary carcinoid tumorlet (PCT) is defined as small proliferation of neuroendocrine cells that invade the adjacent basement membrane. It is often associated with chronic pulmonary inflammatory processes. However, the characteristics of PCT in end-stage lung diseases remain unclear. METHODS: We conducted a retrospective cohort study of the explanted lungs after transplantation at our institution between January 1999 and October 2020. Patients who underwent re-transplantation were excluded. RESULTS: Pulmonary carcinoid tumorlet was incidentally discovered in the explanted lungs from 15 patients (1.1%) out of 1367 lung transplants performed during the study period. Nine patients (60.0 %) were women, with a median age of 59 years (IQR: 57-62) at transplant. Underlying pulmonary indications for lung transplantation were chronic obstructive pulmonary disease (9/15, 60.0%), interstitial lung disease (2/15, 13.0%), pulmonary vascular disease (2/15, 13.0%), alpha-1 antitrypsin deficiency (1/15, 7.0%), and bronchiectasis (1/15, 7.0%). Of the patients who underwent bilateral lung transplantation (13/15, 86.7%), PCT was found in the right lung in 10 patients (10/13, 76.9%). Thirteen patients had one lesion, 1 patient had 2 lesions and 1 patient had multiple lesions. CONCLUSION: Our study shows that PCT is generally uncommon, but when it occurs, it occurs more frequently on the right side and in female patients with end-stage pulmonary disease. Chronic obstructive pulmonary disease may be a predisposing factor for developing PCT.

History of Lung Transplantation.

Lung transplantation remains the only available therapy for many patients with end-stage lung disease. The number of lung transplants performed has increased significantly, but development of the field was slow compared with other solid-organ transplants. This delayed growth was secondary to the increased complexity of transplanting lungs; the continuous needs for surgical, anesthetics, and critical care improvements; changes in immunosuppression and infection prophylaxis; and donor management and patient selection. The future of lung transplant remains promising: expansion of donor after cardiac death donors, improved outcomes, new immunosuppressants targeted to cellular and antibody-mediated rejection, and use of xenotransplantation or artificial lungs.

Outcomes of Extracorporeal Membrane Oxygenation for Primary Graft Dysfunction After Lung Transplantation.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of death in the first 30 days after lung transplantation and is also associated with worse long-term outcomes. Outcomes of patients with PGD grade 3 requiring extracorporeal membrane oxygenation (ECMO) support after lung transplantation have yet to be well described. We sought to describe short- and long-term outcomes for patients with PGD grade 3 who required ECMO support. METHODS: This is a single-center retrospective cohort study of patients undergoing lung transplantation. We stratified patients with PGD grade 3 into non-ECMO, venoarterial (VA) ECMO, and venovenous (VV) ECMO groups after transplantation. We then compared the outcomes between the groups. RESULTS: Of 773 lung transplant recipients, PGD grade 3 developed in 204 (26%) at any time in the first 72 hours after lung transplantation. Of these, 13 (5%) required VA ECMO and 25 (10%) required VV ECMO support. The 30-day, 1-year, and 5-year survival in the VA ECMO group was 62%, 54%, and 43% compared with 96%, 84%, and 65% in the VV ECMO group and 99%, 94%, and 71% in the non-ECMO group. Multivariable Cox regression analysis showed that VA ECMO was associated with increased mortality (hazard ratio, 2.37; 95% CI, 1.06-5.28; P = .04). CONCLUSIONS: Patients who required VA ECMO support for PGD grade 3 have significantly worse survival compared with those who did not require ECMO and those who required VV ECMO support. This suggests that VA ECMO treatment of patients with PGD grade 3 after lung transplantation can be a predictable risk factor for mortality.

Surgical results of the Lung Cancer Mutation Consortium 3 trial: A phase II multicenter single-arm study to investigate the efficacy and safety of atezolizumab as neoadjuvant therapy in patients with stages IB-select IIIB resectable non-small cell lung cancer.

OBJECTIVE: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery. METHODS: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0. RESULTS: From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached. CONCLUSIONS: Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer.

Acute Interstitial Pneumonia (Hamman-Rich Syndrome) in Lung Transplantation: A Case Series.

BACKGROUND: Acute interstitial pneumonia (AIP), also known as Hamman-Rich syndrome, is a rare and rapidly progressive idiopathic interstitial lung disease with a high mortality rate. Treatment is limited to supportive care and empirical high-dose steroids; however, outcomes are generally poor. There are few reports of lung transplantation (LTx) in patients with AIP. METHODS: We retrospectively identified patients with AIP among those who underwent LTx at our center between January 2008 and December 2020. RESULTS: During the study period, 4 patients with AIP underwent bilateral LTx: 3 men and 1 woman, between 30 and 57 years of age. The lung allocation score ranged between 71 and 89. Of the 4 patients, 2 needed extracorporeal membrane oxygenation and mechanical ventilation (MV) and 1 needed MV preoperatively. Time of onset to transplant ranged from 1 to 3 months. None of the patients had primary graft dysfunction after LTx; 2 had acute cellular rejection and 1 had chronic lung allograft dysfunction. The 4 patients are alive with survival ranging between 1 and 12 years after LTx. CONCLUSION: AIP should be considered in patients with acute respiratory failure without a clear etiology. Our study showed that LTx led to good outcomes and should be considered as a treatment option in appropriate candidates.

Bleeding and thrombotic complications associated with anticoagulation prior to lung transplantation: a case series.

Background: Scarce data is available on therapeutic anticoagulation (AC) in patients undergoing pulmonary transplantation. We describe our institutional experience with AC-induced coagulopathy in recipients at the time of transplantation and evaluate its impact on posttransplant outcomes. Methods: Records of adult patients on therapeutic AC at the time of lung transplantation from January 2014 to July 2021 were reviewed. Administration of preoperative pharmacologic reversal was assessed, with adequate reversal defined as international normalized ratio (INR) ≤1.5. We evaluated the incidence of major bleeding complications [delayed sternal closure, reoperation due to bleeding, chest tube output ≥1,500 cc, ≥4 units of packed red blood cells, ≥4 units of platelets, or ≥5 units of fresh frozen plasma (FFP)], major thrombotic complications [venous thromboembolism (VTE) or other major thrombosis on imaging], and inpatient mortality. Results: Of 602 lung transplant recipients, 10 patients taking preoperative warfarin were included in the study. While most patients received pharmacologic reversal preoperatively (n=9, 90%), successful reversal was rarely achieved (n=3, 30%). Inadequate INR reversal was associated with major bleeding events (n=6, 60%). Major thrombotic complications were more frequent (n=7, 70%) than bleeding events. Notably, all fatalities within the cohort (n=2, 20%) were associated with thrombotic, but not bleeding, complications. Conclusions: This is the first known report on the incidence and impact of AC-induced coagulopathy in patients undergoing lung transplantation. Major thrombotic events are frequent and associated with high mortality. Routine surveillance and treatment may be warranted.

Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial.

In an ongoing, open-label, single-arm phase II study ( NCT02927301 ), 181 patients with untreated, resectable, stage IB-IIIB non-small cell lung cancer received two doses of neoadjuvant atezolizumab monotherapy. The primary end point was major pathological response (MPR; ≤10% viable malignant cells) in resected tumors without EGFR or ALK alterations. Of the 143 patients in the primary end point analysis, the MPR was 20% (95% confidence interval, 14-28%). With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80% was encouraging. The most common adverse events during the neoadjuvant phase were fatigue (39%, 71 of 181) and procedural pain (29%, 53 of 181), along with expected immune-related toxicities; there were no unexpected safety signals. In exploratory analyses, MPR was predicted using the pre-treatment peripheral blood immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive of MPR in the peripheral blood were also identified in the tumor microenvironment and were associated with MPR. This study of neoadjuvant atezolizumab in a large cohort of patients with resectable non-small cell lung cancer was safe and met its primary end point of MPR ≥ 15%. Data from this single-arm, non-randomized trial suggest that profiles of innate immune cells in pre-treatment peripheral blood may predict pathological response after neoadjuvant atezolizumab, but additional studies are needed to determine whether these profiles can inform patient selection and new therapeutic approaches.

A comparison of outcomes after lung transplantation between European and North American centers.

BACKGROUND: With advancements in basic science and clinical medicine, lung transplantation (LT) has evolved rapidly over the last three decades. However, it is unclear if significant regional variations exist in long-term outcomes after LT. METHODS: To investigate potential differences, we performed a retrospective, comparative cohort analysis of adult patients undergoing deceased donor single or double LT in North America (NA) or Europe between January 2006 and December 2016. Data up to April 2019 were abstracted from the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Registry. We compared overall survival (OS) between North American and European LT centers in a propensity score matched analysis. RESULTS: In 3,115 well-matched pairs, though 30-day survival was similar between groups (NA 96.2% vs Europe 95.4%, p = 0.116), 5-year survival was significantly higher in European patients (NA 60.1% vs Europe 70.3%, p < 0.001). CONCLUSIONS: This survival difference persisted in a sensitivity analysis excluding Canadian patients. Prior observations suggest that these disparities are at least partly related to better access to care via universal healthcare models prevalent in Europe. Future studies are warranted to confirm our findings and explore other causal mechanisms. It is likely that potential solutions will require concerted efforts from healthcare providers and policymakers.