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Objectifying donor lung quality is difficult and currently there is no consensus. Several donor scoring systems have been proposed in recent years. They all lack large‐scale external validation and widespread acceptance. A retrospective evaluation of 2201 donor lungs offered to the lung transplant program at the Medical University of Vienna between January 2010 and June 2018 was performed. Five different lung donor scores were calculated for each offer (Oto, ET, MALT, UMN‐DLQI, and ODSS). Prediction of organ utilization, 1‐year graft survival, and long‐term outcome were analyzed for each score. 1049 organs were rejected at the initial offer (group I), 209 lungs declined after procurement (group II), and 841 lungs accepted and transplanted (group III). The Oto score was superior in predicting acceptance of the initial offer (AUC: 0.795; CI: 0.776–0.815) and actual donor utilization (AUC: 0.660; CI: 0.618–0.701). Prediction of 1‐year graft survival was best using the MALT score, Oto score, and UMN‐DLQI. Stratification of early outcome by MALT was significant for length of mechanical ventilation (LMV), PGD3 rates, ICU stay and hospital stay, and in‐hospital‐mortality, respectively. To the best of our knowledge, this study is the largest validation analysis comparing currently available donor scores. The Oto score was superior in predicting organ utilization, and MALT score and UMN‐DLQI for predicting outcome after lung transplantation., In this large retrospective analysis, the authors compare several available donor scores and their utility in predicting lung offer acceptance, lung utilization, and postoperative outcomes.

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 (PIP), 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 (PIP, 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.

Background Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research.

[Background & Aims]: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown. [Methods]: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes. [Results]: Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes. [Conclusions]: We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches., This work was supported by the Deutsche Forschungsgemeinschaft (grants AL 1174/4-1, AL1174/4-2, and Collaborative Research Center 1321 “Modeling and Targeting Pancreatic Cancer” to Hana Algül; SFB824 Z2 to Katja Steiger), the Deutsche Krebshilfe (grant 111646 to Hana Algül), a Ramon y Cajal Merit Award from the Ministerio de Economía y Competitividad, Spain (to Bruno Sainz Jr), a Coordinated Grant from Fundación Asociación Española Contra el Cáncer (GC16173694BARB to Bruno Sainz Jr), funding from The Fero Foundation (to Bruno Sainz Jr), and a Proyecto de Investigacion de Salud, ISCIII, Spain (no. PI18/00757 to Bruno Sainz Jr). Jiaoyu Ai is supported by the “China Scholarship Council” grant program.

Objectives The current score for primary graft dysfunction after lung transplantation relies heavily on chest radiographs, and radiologic judgment can make the difference between the lowest (primary graft dysfunction 0) and the highest (primary graft dysfunction 3) grade. This study aimed to evaluate interobserver variability of the scoring of postoperative chest radiographs and its impact on primary graft dysfunction grades in a large single-center cohort. Methods We retrospectively analyzed 497 lung transplantations performed between January 2010 and July 2016 at the Medical University of Vienna. Five trained thoracic radiologists were asked to independently examine postoperative chest radiographs performed at 0 to 6 hours, 24 hours, 48 hours, and 72 hours after arrival at the intensive care unit. Interobserver variability was calculated using Fleiss' kappa (κ) statistics. Results A total of 1988 chest radiographs were evaluated. Consensus among all 5 radiologists was found in only 826 cases (43.0%). At 0 to 6 hours and 24 hours, only a moderate agreement was found among the 5 radiologists (κ = 0.456 and 0.456, respectively), and agreement was even worse at 48 and 72 hours (κ = 0.405 and κ = 0.409). On the basis of this high interobserver variability, best and worst case scenarios were calculated leading to primary graft dysfunction 3 rates of 8.4% versus 28.4% at 0 to 6 hours, 1.8% versus 4.8% at 24 hours, 2.0% versus 5.3% at 48 hours, and 0.2% versus 3.1% at 72 hours. A high recipient body mass index and size-reduced transplants were found to be factors associated with higher rates of interobserver variability. Conclusions The substantial interobserver variability found in this retrospective analysis underlines the difficulty to adequately grade post-transplant organ function. Future revisions of the primary graft dysfunction grading should take this problem into consideration.

Purpose Acceptance rates of donor lungs differ substantially among transplant centers. This is mainly due to a lack of standardized functional parameters of the donor lungs, which can predict organ function after lung transplantation (LTx). Methods A prospective evaluation of lung donors were performed in three transplant centers between January 2017 and September 2018. Standardized ventilation settings were used to collect respiratory and hemodynamic parameters at the time of retrieval. Duration of mechanical ventilation after lung transplantation was defined as the primary end-point. Results A total of 151 lung donors were included in the study. Median donor age was 46 (12-80), median intubation time was 3 days (1-34), 44 (29.1%) donors had smoking history and 19 (12.6%) had chest trauma. At time of retrieval median P/F ratio was 413 mmHg (79-650), median dynamic compliance 45 ml/mbar (14-121) and median pCO2 40 (19-77). In 10 (6.6%) cases, purulent secretions were found during bronchoscopy. In 6 (3.9%) cases evaluation with EVLP followed organ retrieval. Median recipient age was 55 (18-69). The indications for LTx were: COPD (n=61, 40.4%), CF (n=38, 25.2%) and ILD (n=30, 19.9%). Median length of mechanical ventilation was 32 hours (range: 4 - 964). At 72 hours only 1 (0.7%) PGD grade 3 was recorded. P/F ratio at time of offer, donor intubation time, smoking history, donor age, P/F ratio and peak pressure at time of retrieval did not correlate with recipient length of mechanical ventilation and hospitalization time. On the contrary, dynamic compliance at the time of retrieval correlated inversely with recipient weaning time (rs= - 0.199, p Conclusion In this multicenter analysis of lung donor parameters and their relevance for early post-transplant outcome, we found that dynamic compliance of donor lungs was the only factor associated with recipient weaning and hospitalization time. This parameter may have the potential to improve organ selection and subsequently increase the donor pool.

Purpose Aspiration is commonly reported in multiorgan donors. According to standard quality criteria, it is seen as a contraindication for lung utilization. However, an increasing number of transplant centers would accept donor lungs with a history of aspiration as long as lung parenchyma quality is not impaired. Data on the short and long-term outcomes of using this group of donor organs is sparse. Methods We analysed 749 patients who received double lung transplantation between January 2010 and June 2018 in our institution. A total of 30 patients were transplanted using donors with conclusive evidence of significant aspiration. Lungs were accepted for transplantation if P/F ratio was above 250mmHg in absence of significant parenchymal consolidations. The remaining 719 patients were used as control group. Short- and long-term outcomes were compared. Results Basic demographic parameters of recipients were comparable. Donors in aspiration group were significantly younger (34±18 years vs 40±16 years, p=0.034) and had a higher rate of peripheral secretions in bronchoscopy (57.1% vs 25.6%, p=0.02) compared to the control group. Other basic donor parameters did not show statistical differences. Posttransplant results were comparable in both groups. Length of mechanical ventilation was similar with a median of 48h (IQR 128) vs 45h (IQR 73) (p=0.748). There was no significant difference of PGD rates across all time points (T0: p=0.419, T24: p=0.289, T48: p=0.774, T72: p=0.939), ICU stay (16 vs 17 d, p=0.917) as well as total length of stay (35 vs 33 d, p=0.687). While long-term graft survival showed a trend towards impaired results for donor lungs with aspiration, this effect did not reach statistical significance. (1 year: 80.0% vs 85.7%, 5 years: 64.5% vs 75.0%, Log Rank: p=0.123). Conclusion Lung transplantation of donor organs with evidence of aspiration can result in excellent early graft function and comparable long-term outcome in the absence of parenchymal changes. Therefore, careful evaluation of these donors is merited.

In the context of personalized oncology, screening for somatic tumor mutations is crucial for prediction of an individual patient's response to therapy. Massive parallel sequencing (MPS) has been suggested for routine diagnostics, but this technology has not been sufficiently evaluated with respect to feasibility, reliability, and cost effectiveness with routine diagnostic formalin-fixed, paraffin-embedded material. We performed ultradeep targeted semiconductor-based MPS (190 amplicons covering hotspot mutations in 46 genes) in a variety of formalin-fixed, paraffin-embedded diagnostic samples of lung adenocarcinoma tissue with known EGFR mutations (n = 28). The samples reflected the typical spectrum of tissue material for diagnostics, including small biopsies and samples with low tumor-cell content. Using MPS, we successfully sequenced all samples, with a mean read depth of 2947 reads per amplicon. High-quality sequence reads were obtained from samples containing ≥10% tumor material. In all but one sample, variant calling identified the same EGFR mutations as were detected by conventional Sanger sequencing. Moreover, we identified 43 additional mutations in 17 genes and detected amplifications in the EGFR and ERBB2 genes. MPS performance was reliable and independent of the type of material, as well as of the fixation and extraction methods, but was influenced by tumor-cell content and the degree of DNA degradation. Using sample multiplexing, focused MPS approached diagnostically acceptable cost rates.

Objectives The value of intraoperative extracorporeal membrane oxygenation (ECMO) in lung transplantation remains controversial. In our department, ECMO has been used routinely for intraoperatively unstable patients for more than 15 years. Recently, we have extended its indication to a preemptive application in almost all cases. In addition, we prolong ECMO into the early postoperative period whenever graft function does not meet certain quality criteria or in patients with primary pulmonary hypertension. The objective of this study was to review the results of this strategy. Methods All standard bilateral lung transplantations performed between January 2010 and June 2016 were included in this single-center, retrospective analysis. Patients were divided into 3 groups: group I—no ECMO (n = 116), group II—intraoperative ECMO (n = 343), and group III—intraoperative and prolonged postoperative ECMO (n = 123). The impact of different ECMO strategies on primary graft function, short-term outcomes, and patient survival were analyzed. Results The use of intraoperative ECMO was associated with improved 1-, 3-, and 5-year survival compared with non-ECMO patients (91% vs 82%, 85% vs 76%, and 80% vs 74%; log-rank P = .041). This effect was still evident after propensity score matching of both cohorts. Despite the high number of complex patients in group III, outcome was excellent with higher survival rates than in the non-ECMO group at all time points. Conclusions Intraoperative ECMO results in superior survival when compared with transplantation without any extracorporeal support. The concept of prophylactic postoperative ECMO prolongation is associated with excellent outcomes in recipients with pulmonary hypertension and in patients with questionable graft function at the end of implantation.