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Rationale: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors. Objectives: We sought to identify donor, recipient, and perioperative risk factors for PGD. Methods: We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours posttransplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression. Measurements and Main Results: A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.6; P ¼ 0.002); FI O 2 during allograft reperfusion (OR, 1.1 per 10% increase in FI O 2 ; 95% CI, 1.0-1.2; P ¼ 0.01); single lung transplant (OR, 2; 95% CI, 1.2-3.3; P ¼ 0.008); use of cardiopulmonary bypass (OR, 3.4; 95% CI, 2.2-5.3; P , 0.001); overweight (OR, 1.8; 95% CI, 1.2-2.7; P ¼ 0.01) and obese (OR, 2.3; 95% CI, 1.3-3.9; P ¼ 0.004) recipient body mass index; preoperative sarcoidosis (OR, 2.5; 95% CI, 1.1-5.6; P ¼ 0.03) or pulmonary arterial hypertension (OR, 3.5; 95% CI, 1.6-7.7; P ¼ 0.002); and mean pulmonary artery pressure (OR, 1.3 per 10 mm Hg increase; 95% CI, 1.1-1.5; P , 0.001). PGD was significantly associated with 90-day (relative risk, 4.8; absolute risk increase, 18%; P , 0.001) and 1-year (relative risk, 3; absolute risk increase, 23%; P , 0.001) mortality. Conclusions: We identified grade 3 PGD risk factors, several of which are potentially modifiable and should be prioritized for future research aimed at preventative strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 00552357). What This Study Adds to the FieldWe performed a multicenter, prospective cohort study of 1,255 lung transplant recipients across 10 US transplant centers. We identified receipt of an organ from a donor with any smoking history, elevated FI O 2 during allograft reperfusion, preoperative sarcoidosis or pulmonary arterial hypertension, use of cardiopulmonary bypass, single lung transplant, large-volume blood product transfusion, elevated pulmonary arterial pressures, and overweight or obese recipient body habitus as risk factors for grade 3 PGD. Several of these risk factors are potentially modifiable, and thus may suggest preventative strategies, whereas other risk factors should be prioritized for future mechanistic research efforts.

Rationale: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors. Objectives: We sought to identify donor, recipient, and perioperative risk factors for PGD. Methods: We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours posttransplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression. Measurements and Main Results: A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.6; P ¼ 0.002); FI O 2 during allograft reperfusion (OR, 1.1 per 10% increase in FI O 2 ; 95% CI, 1.0-1.2; P ¼ 0.01); single lung transplant (OR, 2; 95% CI, 1.2-3.3; P ¼ 0.008); use of cardiopulmonary bypass (OR, 3.4; 95% CI, 2.2-5.3; P , 0.001); overweight (OR, 1.8; 95% CI, 1.2-2.7; P ¼ 0.01) and obese (OR, 2.3; 95% CI, 1.3-3.9; P ¼ 0.004) recipient body mass index; preoperative sarcoidosis (OR, 2.5; 95% CI, 1.1-5.6; P ¼ 0.03) or pulmonary arterial hypertension (OR, 3.5; 95% CI, 1.6-7.7; P ¼ 0.002); and mean pulmonary artery pressure (OR, 1.3 per 10 mm Hg increase; 95% CI, 1.1-1.5; P , 0.001). PGD was significantly associated with 90-day (relative risk, 4.8; absolute risk increase, 18%; P , 0.001) and 1-year (relative risk, 3; absolute risk increase, 23%; P , 0.001) mortality. Conclusions: We identified grade 3 PGD risk factors, several of which are potentially modifiable and should be prioritized for future research aimed at preventative strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 00552357). What This Study Adds to the FieldWe performed a multicenter, prospective cohort study of 1,255 lung transplant recipients across 10 US transplant centers. We identified receipt of an organ from a donor with any smoking history, elevated FI O 2 during allograft reperfusion, preoperative sarcoidosis or pulmonary arterial hypertension, use of cardiopulmonary bypass, single lung transplant, large-volume blood product transfusion, elevated pulmonary arterial pressures, and overweight or obese recipient body habitus as risk factors for grade 3 PGD. Several of these risk factors are potentially modifiable, and thus may suggest preventative strategies, whereas other risk factors should be prioritized for future mechanistic research efforts.

Tissue resident memory T cells (TRM) maintain immunity in diverse sites as determined in mouse models, while their establishment and role in human tissues has been difficult to assess. Here, we investigated human lung TRM generation, maintenance and function in airway samples obtained longitudinally from HLA-disparate lung transplant recipients, where donor and recipient T cells could be localized and tracked over time. Donor T cells persist specifically in the lungs (and not blood) of transplant recipients and express high levels of TRM signature markers including CD69, CD103, and CD49a, while lung-infiltrating recipient T cells gradually acquire TRM phenotypes over months in vivo. Single cell transcriptome profiling of airway T cells reveals that donor T cells comprise two TRM-like subsets with varying levels of expression of TRM-associated genes while recipient T cells comprised non-TRM and similar TRM-like subpopulations, suggesting de novo TRM generation. Transplant recipients exhibiting higher frequencies of persisting donor TRM experienced fewer adverse clinical events such as primary graft dysfunction and acute cellular rejection compared to recipients with low donor TRM persistence, suggesting that monitoring TRM dynamics could be clinically informative. Together, our results provide novel spatial and temporal insights into how human TRM develop, function, persist, and impact tissue integrity within the complexities of lung transplantation.

Rationale: Functional studies may be useful to predict survival in idiopathic pulmonary fibrosis (IPF). Various cutoffs of 6-min-walk distance (6MWD) have been suggested to identify patients at a high risk of death. Objectives: To examine the association between 6MWD and survival in patients with IPF listed for lung transplantation, and to identify sensitive and specific cutoffs for predicting death at 6 mo. Patients with a walk distance less than 207 m had a more than fourfold greater mortality rate than those with a walk distance of 207 m or more, despite adjustment for demographics, anthropomorphics, FVC % predicted, pulmonary hypertension, and medical comorbidities (adjusted rate ratio, 4.7; 95% confidence interval, 2.5-8.9; p Ͻ 0.0001). 6MWD was a significantly better predictor of 6-mo mortality than was FVC % predicted (c-statistic ϭ 0.73 vs. 0.59, respectively; p ϭ 0.02). Conclusions: Lower 6MWD was strongly and independently associated with an increased mortality rate for wait-listed patients classified as having IPF. 6MWD was a better predictor of death at 6 mo than was FVC % predicted. Keywords: cohort; exercise test; lung diseases, interstitial; lung transplantationIdiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology characterized histopathologically by usual interstitial pneumonia. Clinically, patients with IPF suffer from progressive respiratory failure, with or without acute exacerbations, and have a median survival of less than 3 yr after diagnosis (1-5). Despite several recent randomized trials, no medical therapy has yet been shown to improve survival in patients with IPF (6-8). Although an uncommon disease with an annual incidence of 7-10 per 100,000 persons, IPF accounts for approximately Lung transplantation at the appropriate point in the disease course may prolong survival in IPF (11); however, the optimal time to proceed with transplantation remains unclear. Previously identified risk factors for death in patients with newly diagnosed IPF include greater age, male gender, lower FVC % predicted, and lower diffusing capacity of carbon monoxide (Dl CO ) % predicted (1, 2, 12-15). Lower peak oxygen consumption during cardiopulmonary exercise testing and oxygen desaturation during 6-min walk testing have also been associated with a higher risk of death in IPF (2,16,17). However, patients with IPF referred and listed for lung transplantation are a distinct cohort. Therefore, extrapolation of survival analyses from patients identified in another context may not be appropriate for decisions regarding the timing of lung transplantation.We recently reported that patients with IPF evaluated for lung transplantation with a 6-min-walk distance (6MWD) less than 350 m had a shorter survival time than those with a 6MWD greater than 350 m (18). Studies of other types of walk tests have shown similar results (19). On the other hand, a recent cohort study of newly diagnosed patients with biopsy-proven idiopathic interstitial pneumonia did not detect an association between 6MWD and...

Rationale: Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation.Objectives: To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates.Methods: In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case-control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively.Measurements and Main Results: Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24-33%) and 10% based on the SPPB (95% CI, 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01-1.67) for FFP and 1.53 (95% CI, 1.19-1.59) for SPPB.Conclusions: Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.Keywords: biomarker; body composition; disability; frailty; lung transplantation Author Contributions: J.P.S., J.M.D., C.J.G., P.D.B., P.P.K., J.D.C., and D.J.L. made substantial contributions to the conception and design of the work; J.P.S. wrote the first draft of the manuscript; and J.P.S., J

Quantification of PD-L1 expression is feasible on cytology specimens, and the results are comparable to those obtained from surgical resection and small biopsy specimens, including in matched specimens and using a single predictive IHC marker. Future studies will be necessary to determine the comparative value of other antibodies and their ability to predict response to immunotherapy. Cancer Cytopathol 2017;125:896-907. © 2017 American Cancer Society.

Background The only definitive treatment for end-stage organ failure is orthotopic transplantation. Lung extracellular matrix (ECM) holds great potential as a scaffold for lung tissue engineering since it retains the complex architecture, biomechanics and topological specificity of the lung. Decellularization of human lungs rejected from transplantation could provide “ideal” biological scaffolds for lung tissue engineering, but the availability of such lungs remains limited. The present study was designed to determine whether porcine lung could serve as a suitable substitute of human lung to study tissue-engineering therapies. Methods Human and porcine lungs were procured, sliced into sheets, and decellularized using three different methods. Compositional, ultrastructural, and biomechanical changes to the ECM were characterized. The suitability of LECM for cellular re-population was evaluated by assessing the viability, growth, and metabolic activity of human lung fibroblasts (hMRC-5s), human small airway epithelial cells (hSAECs), and human adipose-derived mesenchymal stem cells (hMSCs) over a period of seven days. Results Decellularization using CHAPS, 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate, showed the best maintenance of both human and porcine LECM, with similar retention of ECM proteins, except for elastin. Human and porcine LECM supported the cultivation of pulmonary cells in a similar way, except that the human LECM was stiffer and resulted in higher metabolic activity of the cells than porcine LECM. Conclusions Porcine lungs can be decellularized using CHAPS to produce lung ECM scaffolds with properties resembling those of human lungs, for pulmonary tissue engineering. We propose that porcine lung ECM can be an excellent screening platform for the envisioned human tissue engineering applications of decellularized lungs.