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Objectives: The oncological equivalence of anatomical segmentectomy for early stage non-small cell lung cancer (NSCLC) is still controversial. Primary aim of this study was survival outcomes in combination with improved quality of life after segmentectomy compared with lobectomy in patients with pathological stage Ia NSCLC (up to 2 cm, 7th edition) Materials and Methods: We conducted a prospective, randomized, multicenter phase III trial to confirm the non-inferiority of segmentectomy to lobectomy in regard to prognosis (trial No. DRKS00004897). Patients were randomized to undergo either segmentectomy or lobectomy and followed up for 5-years survival and tumor recurrence. The 5-year hazard ratio comparing lobectomy with segmentectomy was required to remain above 0.5. Results: Between October 2013 and June 2016, 108 patients with verified or suspected NSCLC up to 2 cm diameter were enrolled; 54 were assigned to lobectomy and 54 (1 drop-out) to segmentectomy. In-hospital and 90 days mortality was 0% in both groups. Overall survival at 5 years was 86.52% in the lobectomy compared to 78.21% in the segmentectomy group (HR = 0.61, (95% CI 0.23–1.66), p-value of non-inferiority test, p-ni = 0.687). Disease free survival was 77.29% for the lobectomy and 77.96% for the segmentectomy patients (HR = 1.50, (95% CI 0.60–3.76), p-ni = 0.019). At a median follow-up of 5 years, no differences were noted in either the locoregional or distant recurrent disease in both groups (9.4% vs 7.4%, p-ni = 0.506). Conclusion: Overall survival, locoregional and distant recurrences was not significantly difference for patients undergoing either segmentectomy or lobectomy for stage Ia NSCLC. The targeted non-inferiority of segmentectomy to lobectomy could not be proven for primary endpoint overall survival, but was significant for the secondary endpoint of disease free survival.

BACKGROUND Cadaveric lobar lung transplantation (L-LTx) is developed to overcome donor-recipient size mismatch. Controversial short- and long-term outcomes following L-LTx have been reported compared to full-sized lung transplantation (F-LTx). This study reports long-term outcomes after L-LTx. METHODS We reviewed patients undergoing lung transplantation (LTx) between 2000 and 2016. The decision to perform L-LTx was made based mainly on donor-recipient height discrepancy and visual assessment of donor lungs. Predicted donor-recipient total lung capacity (TLC) ratio was calculated more recently. Primary outcome was overall survival. RESULTS In all, 370 bilateral LTx were performed during the study period, among those 250 (67%) underwent F-LTx and 120 (32%) underwent L-LTx, respectively. One- and 5-year survival rates were 85% vs. 90% and 53% vs. 63% for L-LTx and F-LTx, respectively (p = 0.16). Chronic lung allograft dysfunction (CLAD)-free survival at 5 years was 48% in L-LTx vs. 51% in F-LTx recipients (p = 0.89), respectively. Age, intraoperative extracorporeal membrane oxygenation (ECMO) use, intensive care unit (ICU) stay, and postoperative renal replacement therapy (RRT) were significant prognostic factors for survival using multivariate analysis. CONCLUSIONS Overall survival and CLAD-free survival following L-LTx were comparable to F-LTx. Given the ongoing donor organ shortage, cadaveric L-LTx remains as an important resource in LTx.

MELD exceptions are designed to equipoise liver transplant waiting list survival. We aimed to analyze the impact of the MELD Upgrade rule and all other MELD exceptions on the liver transplant waiting list outcomes during 2012-2017 in Switzerland.We conducted a nationwide cohort study including all adult patients registered on the Swiss liver transplant waiting list between 2012 and 2017. Waiting list mortality and access to transplantation were analyzed, considering MELD exceptions as time-dependent covariates.730 patients were included. Patients with MELD Upgrade exceptions had a higher risk of dying while on the waiting list (OR 2.13; CI 95% 1.30-3.47) and also an increased likelihood of receiving a liver transplantation, when compared to patients without MELD exceptions. Patients with any type of MELD exceptions were more likely to be transplanted when compared to patients without MELD exceptions. The proportion of patients with MELD exceptions increased from 2012 to 2017 (44% vs 88%). Allocation MELD at the time of transplantation showed an annual increase (23 ± 8 points vs 32 ± 5 points, p 0.001).Only patients with MELD Upgrade exceptions had the expected combination of higher waiting list mortality and quicker access to liver transplantation.

OBJECTIVES No significant data are available to assess whether complex sleeve lobectomy (complex-SL) can be considered comparable to conventional lobectomy (CL) in terms of surgical outcome. The purpose of this study was to compare surgical and oncological outcomes of complex-SL with CL in patients with lung cancer. METHODS Between 2000 and 2015, a total of 568 patients who underwent open CL (defined as resection of only 1 lobe) and 187 patients who underwent SL were analysed. The SL group was divided into 2 subgroups: standard-SL (bronchial SL, n = 106) and complex-SL (n = 81) (defined as bronchial sleeve resection together with another surgical intervention: bronchovascular SL, n = 40; vascular SL, n = 26; atypical bronchoplasty with resection of more than 1 lobe, n = 12; bronchial SL + chest wall resection, n = 3). RESULTS The complex-SL group had more patients with chronic obstructive pulmonary disease (COPD) (25.9% vs 12.5%, P = 0.001), neoadjuvant treatment (39.5% vs 12.0%, P CONCLUSIONS Complex-SL had a comparable outcome to CL, although the complex-SL group had more patients with advanced-stage NSCLC, low preoperative forced expiratory volume in 1 s and COPD.

Background: Data on individualized immunosuppressive protocols for the pediatric heart recipients are missing in Europe. To contribute to this very small but specialized field, we describe the use of induction therapy (IT) in pediatric heart transplant patients in Switzerland and the retrospective outcomes. Method: This is a retrospective national database analysis of children

BACKGROUND We aimed to analyse the nodal spread of our non-small cell lung cancer pN2 cohort according to tumour location, the possible implications of an unusual spreading pattern, and other factors influencing postoperative survival after anatomical lung resection. METHODS In this retrospective observational study, clinical data was collected for 124 consecutive non-small cell lung cancer (NSCLC) patients with a pathological N2 (stage IIIA or B) undergoing anatomical lung resection at our institution between 2001 and 2010. Cox regression was used to analyse independent predictors of 5-year overall survival and recurrence-free survival. RESULTS A total of 105 patients were included in the final analysis. Tumour location in the right upper lobe and middle lobe was significantly more often associated with involvement of lymph node stations 2 and 4 than NSCLC in the right lower lobe (station 2: right upper vs right lower lobe, p = 0.001 and middle vs right lower lobe, p = 0.038; station 4: right upper vs right lower lobe, p

(a) Activity-based proteome profiling (ABPP) probes combined with mass spectrometry (MS) is the tool of functional proteomics for the quantification of catalytically active enzymes. Here, we applied a depletion-dependent ABPP for serine hydrolase (SH) profiling in 30-μm thickness cryosections of optimal-cutting-temperature (OCT)-embedded tissue of advanced lung adenocarcinomas (LUAD). (b) For the proof-of-concept, we profiled SH activities in advanced LUAD disease. We retrospectively analyzed hydrolase activity differences with prognostic values related to aggressive phenotype based on clinical data collected over the course of disease progression. Interestingly, detection of proteins correlating by active-enzyme capture uncover their functional links with the metabolic SHs related to the enhanced palmitoylation-depalmitoylation cycle of lipoproteins in aggressive LUAD. In contrast, the standard DDA-MS analysis of on-bead-depleted enzymes detected 95 SH’s of which less than 60 enzymes were quantified based on spectral counting. (c) We found enhanced activities of dozen SHs in all LUAD tumors. Remarkably, the activity of 11 hydrolases emphasized by IAH1, ABHD12, LYPLA2 and MST1 discriminate aggressive tumors at the time of diagnosis. Functional analysis leveraging enzymes and associated co-depleted proteins revealed catabolic processing of lipoproteins and enrichment of enzymes displaying increased de-palmitoylase activities. This is interesting because multiple isoforms of RAS protein (K-RAS, H-RAS and N-RAS), the most frequently mutated oncogene in human cancers including LUAD (i.e. 30% of LUADs contain somatic K-Ras mutation), attain oncogenic properties only in depalmitoylated state which favor protein intracellular trafficking by detachment from hydrophobic plasma membrane. In line, mutant K-Ras protein co-localize on outer mitochondrion membrane and interact with glycolytic enzymes (hexokinase-1 and -2) only in depalmitoylated state. This interaction induce K-Ras oncogenic properties and increased glucose uptake and glycolysis even in the presence of abundant oxygen (Warburg effect). Curiously, we observed co-depletion of mitochondrial proteins including glycolytic hexokinase 2 with several lipases displaying increase depalmitoylase activity in short LUAD survivals. (d) Surprisingly, an evident disagreement in the activity of enzymes involved in lipolysis and protein depalmitoylation (i.e. IAH1, ABHD12, LYPLA2) was discovered between LUAD survival subtypes. These essential metabolic differences were uncovered by our standard proteomic analysis and to our knowledge have not been reported. Since the inhibitors of serine lipases are promising targets in other RAS-mutant carcinomas, this metabolic vulnerabilities discovered in aggressive LUAD can be explored as promising therapeutic strategies in lung cancer. Citation Format: Tatjana Sajic, Stephan Arni, Rudolf Aebersold, Sven Hillinger. Discrimination of aggressive tumor profiles in lung adenocarcinomas using activity based protein profiling by SWATH/DIA-MS mode [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1887.

Background: Radiotherapy is recommended as primary local therapy for inoperable patients with non-small cell lung cancer (NSCLC). We hypothesized that selected patients with advanced emphysema could be candidates for surgery and improved functional outcome might result in addition to low mortality and morbidity and successful cancer control when sublobar resection in a lung volume reduction surgery (LVRS) concept is applied. Methods: All patients with NSCLC and severe emphysema who underwent cancer resection in a LVRS concept between 2003 and 2015 were included for analysis. Postoperative 90-day mortality, complications, survival and lung function with forced expiratory volume in one second pre-operatively and three months postoperatively served as endpoints. Results: Fourteen patients were included. Three procedures were bilateral and eleven unilateral, eight have been performed with thoracoscopy and six with conversion to an open procedure due to adhesions. In ten patients, tumor resection was atypical and in four patients an anatomic segmentectomy was performed. All patients had lung volume reduction. Prolonged air leak occurred in three patients. Perioperative 90-mortality was zero. Median pre-operative forced expiratory volume in one second was 32.5% and increased to 37% (P=0.002) 3 months following surgery. Three and 5-year survival rates were 50% and 35%, respectively. Conclusions: Sublobar resection of NSCLC combined with LVRS in patients with severely impaired lung function due to emphysema can be performed with low mortality and morbidity making it an alternative treatment modality to radiotherapy. This approach allows cancer resection in marginal patients and improves emphysema symptoms simultaneously.

Purpose: To assess various volume based PET quantification metrics including: metabolic tumor volume (MTV) and total lesion glycolysis (TLG) with different thresholds as well as background activity based PET metrics (Background Subtracted Lesion activity (BSL) and Volume (BSV)) as prognostic markers for progression free and overall survival (PFS, OS) in early stage I and II non-small cell lung cancer (NSCLC) after resection. Patients and Methods: 133 patients received an adequate FDG PET/CT scan prior to surgery between January 2003 and December 2010. All PET activity metrics showed a skewed distribution and were log-transformed before calculating the Pearson correlation coefficients (PCC). Survival tree analysis was used to discriminate between high and low risk patients and to select the most important prognostic markers. Akaike information criterion (AIC) was used to compare two uni-variate models. Results: Within the study time 36 patients died from NSCLC and 26 patients from other causes. At the end of follow up 70 patients were alive, with 67 patients being free of disease. All log-transformed PET metrics showed a very strong linear association with a PCC between 0.703-0.962. After multiple testing corrections only one prognostic marker contributed a significant split point in the survival tree analysis. Out of 10 potential predictors including 7 PET metrics BSL>6852 (P = 0.017) was chosen as split point assigning 13 patients into a high risk group. If BSL was removed from the set of predictors TLG42% >4204 (P = 0.023) was chosen as split point. Using a dichotomized BSL or TLG42% variable for an uni-variate Cox model the AIC-difference of both models was smaller than 2, therefore the data do not provide evidence that one of the two prognostic factors is superior. Conclusion: Volume based PET metrics do correlate with PFS and OS and could be used for risk assessment in stage I-II NSCLC. The different PET metrics assessed in this study showed a very high correlation; therefore, it is not surprising that there was no significant difference to predict PFS or OS within this study. Overall, Patients with large and metabolically active tumors should be considered high risk and might need further treatment after resection. Since all analysis steps were done with the same data these results should be validated on new patient data.

Hydatosis is a clinical entity known since the time of Hippocrates with Echinococcus granulosus as most common cause of hydatidosis. Humans as well as herbivores are infected as intermediate hosts and the zoonosis is most commonly observed in the liver and lungs. Intrathoracic extrapulmonary cysts are uncommon. We present the rare presentation of concomitant intrathoracic extrapulmonary and cervical hydatid cysts after a follow-up of 10 years. The patient presented with a soft palpable supraclavivular mass and increasing pain. Thoracoscopic exploration (VATS, video-assisted thoracic surgery) revealed a cystic lesion at the apex of the left hemithorax without contact to the lung. We performed a cystotomy and removed the laminated membrane. Later, the cervical hydatid cyst was removed. Five years later, a recurrence of the disease was again resected. Currently, 10 years after initial referral, the patient remains without any signs of active disease. To our knowledge, this is the first report of an intrathoracic extrapulmonary hydatidosis removed by VATS. Our report presents VATS as a surgical option in the treatment of intrathoracic extrapulmonary hydatid disease of the thoracic apex and confirms the feasibility of minimal invasive surgery for intrathoracic hydatid disease.

BACKGROUND Radiomics is a promising tool for the identification of new prognostic biomarkers. Radiomic features can be affected by different scanning protocols, often present in retrospective and prospective clinical data. We compared a computed tomography (CT) radiomics model based on a large but highly heterogeneous multicentric image dataset with robust feature pre-selection to a model based on a smaller but standardized image dataset without pre-selection. MATERIALS AND METHODS Primary tumor radiomics was extracted from pre-treatment CTs of IIIA/N2/IIIB NSCLC patients from a prospective Swiss multicentric randomized trial (npatient = 124, ninstitution = 14, SAKK 16/00) and a validation dataset (npatient = 31, ninstitution = 1). Four robustness studies investigating inter-observer delineation variation, motion, convolution kernel, and contrast were conducted to identify robust features using an intraclass correlation coefficient threshold >0.9. Two 12-months overall survival (OS) logistic regression models were trained: (a) on the entire multicentric heterogeneous dataset but with robust feature pre-selection (MCR) and (b) on a smaller standardized subset using all features (STD). Both models were validated on the validation dataset acquired with similar reconstruction parameters as the STD dataset. The model performances were compared using the DeLong test. RESULTS In total, 113 stable features were identified (nshape = 8, nintensity = 0, ntexture = 7, nwavelet = 98). The convolution kernel had the strongest influence on the feature robustness (

Purpose Postoperative cause of death in lung transplantation and time to its occurrence is reported occasionally. This study investigated all causes of death in our lung transplant recipients. Methods All recipients transplanted between 1992 and 2018 were included. Follow-up date was October 2019. Median (min-max) survival was calculated to compare tendencies of incidence between groups. Results Among all 521 transplantations performed, 333 recipients (63.9%) died. Median time from transplantation to death was 40 (0-278) months. Deaths which occurred within 1 month after transplantation were predominantly due to primary graft dysfunction (N=15, 4.5%), followed by cytomegalovirus infection (N=9, 2.7%), major bleeding (N=6, 1.8%) and idiopathic hyperammonemia (N=4, 1.2%). Among all non-cytomegalovirus-infections (N=63, 19.9%), pneumonia (N=36, 10.8%) was the major cause of death, followed by colon perforation (N=12, 3.6%) and cholangitis (N=4, 1.2%). Observation time was median 21(0-230), 11.5(1-278) and 55(28-122) months, respectively. Among patients with malignomas, death due to lymphoma (N=10, 3.0%) occurred after a median of 29.5(12-67) months, death due to carcinoma (N=36, 10.8%) after 92(19-219) months. Cerebrovascular insult/bleeding led to 13 deaths (3.9%) after a median of 9(0-181) months. Death due to acute rejection (N=4, 1.2%) was observed at a median of 9(0-45) months. Chronic lung allograft dysfunction (CLAD) was diagnosed in 129 cases (38.7%), being the largest group with CLAD only as cause of death in 77 patients at a median onset of 53(5-246) months; CLAD and additional infection (N=44, 13.2%) median onset 39(5-145) months; CLAD and additional multi organ dysfunction (N=8, 2.4%) median onset 78(18-198) months. Cardiac (N=19, 5.7%) and renal failures (N=5, 1.5%) occurred late: median 103(0-271) months and 84(17-150) months, respectively. Conclusion There is a large variety of causes of death after lung transplantation with a dominant role of infection, CLAD and carcinoma. With increasing follow-up time, infection becomes less prevalent and CLAD and carcinoma are observed more frequently.

Introduction Lobar lung transplantation (LLTx) allows the use of oversized grafts for small recipients. In this technically demanding and not widely adopted procedure, prolonged air leak, kinking of vascular anastomoses and remaining dead space are frequent complications. We describe our experience in treatening the rarely reported bronchial stump insu!cency (BSI) after LLTx. Case Report Between 1993-2016 we performed 120 cases of LLTx in our center. Among these, 3 developed BSI with empyema. A) 48 year old female with Langerhanscell histiocytosis and BSI of the resected left lower lobe; B) 44 year old male with cystic fibrosis and BSI of the resected right lower lobe; C) 62 year old male with idiopathic pulmonary fibrosis and BSI of the resected right lower lobe. Occurrence of fistula was observed 78 days, 29 days and 39 days after LLTx in A, B and C, respectively. The 3 cases underwent accelerated treatment, consisting of radical debridement of the pleural cavity, packing with wet dressings of diluted 10% povidoneiodine, closure of the bronchial fistula, repeated change of dressings every 2 to 3 days until the chest is macroscopically clean and finally reinforcement of the stump with omentoplasty. Four surgical steps were necessary in case A and C, two in case B. Case A and B recovered well within 6 and 3 days of ICU and had 22 and 39 days overall re-hospitalization, respectively. Case C died 10 days after successful fistula revision due colitis with sepsis in aplasia. Summary A prominent bronchus stump after lower lobectomy in LLTx may cause secretion congestion and focal inflammation that results in BSI. Due to anatomical reasons, a bronchus stump may not be avoided in case of LLTx with right lower lobe resection. Insufficiency can be treated successfully utilizing a multiple stage procedure with suture of the bronchus and covering with omentum flap.

Background Extracorporeal life support (ECLS) as a bridge to lung retransplantation has been reported only anecdotally. Thus, we analyzed combined data from our center with pooled data from published studies to identify selection criteria for this advanced therapy. Methods Four patients at our center were bridged on ECLS to lung retransplantation. Patient data were retrospectively retrieved from electronic records. The MEDLINE database was searched using the PubMed engine and yielded 13 relevant studies that included a minimum of 3 patients bridged to lung retransplantation, and four studies described detailed data on 17 patients. Patient data from our center (n = 4) were pooled with data from the MEDLINE database (n = 17) and analyzed. Results Of 21 patients, 3 (14%) died on ECLS awaiting retransplantation, and 18 (86%) underwent retransplantation after a median of 37 months (range, 0 to 168 months) after primary transplantation. Type of ECLS was extracorporeal carbon dioxide removal (ECCO2R) in 4, venovenous extracorporeal membrane oxygenation (ECMO) in 7, venoarterial ECMO in 5, or was not mentioned in 2. The 90-day postoperative mortality was 28%. Overall 1-year survival was 48%. Patients bridged to retransplantation with ECCO2R/venovenous ECMO ( p = 0.05) or on awake ECMO ( p = 0.06) showed strong trends toward better survival in univariate analysis. Univariate and multivariate analysis identified a longer intertransplant interval as a statistically significant favorable prognostic factor. In a selected subgroup of patients (awake ECCO2R/venovenous ECMO support and intertransplant interval >2 years), 1-year survival reached 67%. Conclusions Despite limited overall 1-year survival for patients bridged with ECLS to lung retransplantation, careful patient selection may yield an acceptable 1-year survival of 67%.

(a) Proteomics relies on protein digestion into smaller fragments/peptides and converge to proteome sequence information, classification, and expression levels without a screen of the cellular protein activities. Activity-based proteome profiling (ABPP) is emerging as a tool for functional proteomics based on mass spectrometry. We established an ABPP-SWATH/DIA MS platform compatible with OCT-embedded biopsies for differential global serine hydrolase (SHs) activity profiling and determine the Relative Depletion-Detected Activity (RDDA) index that reflects the relative activity of SHs in type IIIA lung adenocarcinoma biopsies. (b) To prevent digestion on streptavidin beads and MS spectra contamination, we used SWATH/DIA-MS2 signal intensities for the assessment of the ratio between the biopsy-extract solution either treated with DMSO or which had earlier been depleted with chemical probe for active enzyme molecules. We processed 24 lung biopsies (having a solution of depleted and non-depleted proteome) of long and short survivors with type IIIA lung adenocarcinoma tumor and their normal tissue counterparts and included peptides of 65 known endogenous inhibitors of SH. In parallel experiments, we analyzed the catalytically depleted part of the molecule by conventional ABPP-MS approach integrated on bead sample digestion. (c) We quantified 117 proteins annotated to the serine hydrolase family, of which as much as 60% was depleted with a CI of 90% in the biopsy-extract solution incubated with chemical probe. Among 133 enzymes monitored over the entire clinical cohort, we found as many as 89 enzymes with significant depletion that we further used to generate the activity SH profiles of each biopsy. We found 36 enzymes exclusively depleted in tumor tissue, both in short and long survivals, and with depletion absent from normal counterparts. By quantification of the catalytically active part of the molecule on the streptavidin bead sample pull-down digest, we found only 9 proteins that contained quality data for spectral counting comparisons. Partial Least Squares Discriminant Analysis (PLS-DA) analysis revealed the activity profiles of 9 enzymes perfectly discriminating the tumor tissues of short survivals, and these enzyme signatures were enhanced by the elevated activity of 2 enzymes - ADH1C and IAH1- in short-term survivors. (d) We have demonstrated that this approach can substantially increase the differential detection of protease activity between oncogenic lung tissue and their normal tissue counterparts. Citation Format: Tatjana Sajic, Stephan Arni, Rudolf Aebersold, Sven Hillinger. Activity based protein profiling by SWATH/DIA-MS mode (ABPP-SWATH/DIA-MS) from OCT-embedded tissues biopsies reveals lung tumor-specific protease profiles [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6482.

Purpose The Charlson-Deyo-Comorbidity-Index is a popular age independent score to predict long term survival. It incorporates 17 weighted comorbidity conditions and is established in a variety of clinical fields. However, the feasibility for lung transplantation is not yet tested. We therefore validate this score for primary graft dysfunction (PGD), short- to long-term survival and onset of chronic allograft dysfunction (CLAD). Methods The Charleston-Deyo-Comorbidity-Index was assessed in all 466 lung transplant recipients at our center between 1992-2015. Discriminative ability was calculated by the area under the ROC curve (AUC) for 30-day to 10-year survival, severe PGD (grade III) and onset of CLAD. An AUC of 0.5 was considered as non-predictive and 1.0 as maximally predictive. Multiple Cox-regression was used to detect independent risk factors for mortality in the score. All calculations were adjusted for unilateral transplantation, retransplantation, recipient age, idiomatic pulmonary fibrosis, preoperative intensive care unit stay and marginality of the donor (Oto-Donor-Score). Results Median Charslon-Deyo-Comorbidity-Index was 1 (range 1-5). PGD had an AUC of 0.65 (95%CI 0.59-0.72). The predictability increased from 30-day AUC0.58 (95%CI 0.48-0.69) over 1-year AUC0.67 (95%CI 0.60-0.73) to 10-year survival AUC0.72 (95%CI 0.67-0.78). A trend of decreased predictability was observed for onset of CLAD at 1-year AUC0.64 (95%CI 0.55-0.76) to 10-years AUC0.60 (95%CI 0.55-0.66). Multiple Cox-regression revealed the following comorbidities of the index as independent risk factors for mortality: congestive heart failure HR1.40 (95%CI 1.01-1.94), coronary disease needing intervention HR1.72 (95%CI 1.10-2.68), end-stage diabetes mellitus HR5.93 (2.12-19.58), moderate liver disease HR2.53 (95%CI 1.71-3.74) and peripheral vascular disease HR2.43 (95%CI 1.18-5.00). Conclusion The Charlson-Deyo-Comorbidity-Index has a fair prediction for PGD, mid-term survival and onset of CLAD and a good prediction for long term survival after lung transplantation. This score might be used for further clinical decision making in lung allocation. A different weighing and sub-categorization may even improve its prediction.

Purpose Although malignancy is considered a common complication after lung transplantation, profound studies about incidence, characterization, risk assessment and morbidity and mortality are scarce. Therefore we analyze all recipients at our center. Methods All 521 lung transplant recipients at our center between 1992 and 2018 were retrospectively assessed for pre-transplant history and post-transplant onset of malignoma (censor date 01.05.2019). The incidence of occurrence was analyzed using Kaplan-Meier survival. Risk factors to develop a malignoma were assessed by multiple Cox-regression. Results During the observation period, 3.1% (N=16) recipients were transplanted with a history of a cured malignoma, not reoccurring within at least 5 years. After transplantation, 3.1% (N=16) recipient developed a lymphoma, 22.1% (N=115) developed skin cancer and 11.7% (N=63) a non-skin-malignoma. Within non-skin-malignomas, gastrointestinal carcinomas (41.3%, N=26) and lung carcinomas (15.9%, N=10) were the predominant groups. Of note, 6 out of 10 lung carcinomas originated from the donor lung. 6.9% (N=36) of the recipients died of malignoma, accounting for 10.8% of all observed deaths (N=333). The incidence of non-skin-malignancies was after 1 year 2.4%, after 5 years 10.5% and after 10 years 24.4%. The incidence of skin cancer was at 1 year 1.8%, at 5 years 16.3% and at 10 years 35.8%. Multiple Cox-regression revealed that age ≥ 50 years (HR2.8; 95%CI 1.7-4.6) and the underlying diseases of emphysema (HR2.9; 95%CI 1.7-4.9) and interstitial pulmonary fibrosis (HR2.5; 95%CI 1.4-4.6) were independent risk factors to develop a non-skin-maligonoma. Conclusion Post-transplant malignancies are an important reason for morbidity and mortality in lung transplantation. Screening for malignancies during follow up is crucial, especially when considering the increasing risk by the current trend toward an older recipient population, underlying diseases with a smoking history as well as extended donor lungs.

Purpose: Utilization of donation after circulatory death (DCD) donors has the potential to decrease donor shortage in lung transplantation (LTx). This study reviews the long-term outcome of LTx from DCD donors. Methods: We included all consecutive DCD (Maastricht Category III) and all donations after brain death (DBD) donor lung transplants at our Center performed between January 2012 and February 2017. Data were analyzed comparing the two groups in regard of survival after LTx as primary outcome. Results: Median withdrawal to cardiac arrest time was 17 min (interquartile range [IQR]: 11.5–20.5). Median cardiac arrest to cold perfusion was 32 min (IQR: 24.5–36.5). Primary graft dysfunction (PGD) grade 3 at T72 occurred in three recipients. Chronic lung allograft dysfunction (CLAD) led to death in two cases. In DCD group, there was no 90-day mortality. In DCD, group 1- and 3-year survival rates were 100% and 80%. In DBD group, 1- and 3-year survival rates were 85% and 69% (p = 0.4). Conclusions: Our report confirmed the comparable outcome from DCD donors compared with DBD donors. Utility of DCD donors is a safe option to overcome donor shortage.

Oncogenic rearrangements leading to targetable gene fusions are well-established cancer driver events in lung adenocarcinoma. Accurate and reliable detection of these gene fusions is crucial to select the appropriate targeted therapy for each patient. We compared the targeted next-generation-sequencing Oncomine Focus Assay (OFA; Thermo Fisher Scientific) with conventional ALK FISH and anti-Alk immunohistochemistry in a cohort of 52 lung adenocarcinomas (10 ALK rearranged, 18 non-ALK rearranged, and 24 untested cases). We found a sensitivity and specificity of 100% for detection of ALK rearrangements using the OFA panel. In addition, targeted next generation sequencing allowed us to analyze a set of 23 driver genes in a single assay. Besides EML4-ALK (11/52 cases), we detected EZR-ROS1 (1/52 cases), KIF5B-RET (1/52 cases) and MET-MET (4/52 cases) fusions. All EML4-ALK, EZR-ROS1 and KIF5B-RET fusions were confirmed by multiplexed targeted next generation sequencing assay (Oncomine Solid Tumor Fusion Transcript Kit, Thermo Fisher Scientific). All cases with EML4-ALK rearrangement were confirmed by Alk immunohistochemistry and all but one by ALK FISH. In our experience, targeted next-generation sequencing is a reliable and timesaving tool for multiplexed detection of targetable rearrangements. Therefore, targeted next-generation sequencing represents an efficient alternative to time-consuming single target assays currently used in molecular pathology.

We present an exemplary case of an immunocompromised patient with pulmonary mucormycosis successfully treated by a combination of surgical removal of the mucor and urokinase to control the recurring hemothorax. The use of urokinase in hemothoraces is a way to reduce repetitive surgeries in weak patients.

Assessment of tumor response after chemotherapy using (18)F-FDG PET metrics is gaining acceptance. Several studies have suggested that the parameters metabolically active tumor volume (MTV) and total lesion glycolysis (TLG) are superior to SUVmax for measuring tumor burden. However, the measurement of MTV and TLG is still controversial; the most common method uses an absolute threshold of 42% of SUVmax Recently, we implemented a background-adaptive method to determine the background-subtracted lesion activity (BSL) and the background-subtracted volume (BSV). In this study, we investigated the correlation between such PET metrics and histopathologic response in non-small cell lung carcinoma (NSCLC).Forty-four NSCLC patients were retrospectively identified. Their PET/CT data on both types of scan before and after neoadjuvant chemotherapy were analyzed regarding SUVmax, MTV, TLG, BSL, and BSV, as well as the relative changes in these parameters. The tumor regression score as an indicator of histopathologic response was scored on hematoxylin- and eosin-stained sections of the surgical specimens using a 4-tiered scale (scores 1-4). The correlation between score and the absolute and relative PET metrics after chemotherapy was analyzed using Spearman rank correlation tests.Tumors that demonstrated a good response after neoadjuvant chemotherapy had significantly lower (18)F-FDG activity than nonresponding tumors (scores 3 and 4: SUVmax, 4.2 [range, 1.8-7.9] vs. scores 1 and 2: SUVmax, 8.1 [range, 1.4-40.4]; P = 0.001). The same was found for change in SUVmax and score (P = 0.001). PET volume metrics based on a 42% fixed threshold for SUVmax did not correlate with score (TLG, P = 0.505; MTV, P = 0.386). However, both of the background activity-based PET volume metrics-BSL and BSV-significantly correlated with score (P0.001 each).PET volume metrics based on background-adaptive methods correlate better with histopathologic tumor regression score in NSCLC patients under neoadjuvant chemotherapy than algorithms and methods using a fixed threshold (42% SUVmax).

Lung transplantation (LTx) is an accepted therapy in children with end-stage lung diseases. Pediatric-specific experience is considered important in pediatric LTx. We present our institutional experience and its outcome since the year 2000, asking whether different treatment strategies produce comparable outcomes in pediatric lung transplant recipients at our predominantly adult center. This is a retrospective analysis of children and adolescents aged ≤20 years, undergoing LTx between January 2001 and December 2013. Minimum follow-up was 12 months. Primary endpoints were re-transplantation or death. We performed 33 lung transplant procedures in 29 patients. Survival 1 month post-operatively was 96.6%, at 3 months 93.1% and at 12 months 82.8%, respectively. At the end of our follow up, 72.4% of our pediatric cohort was still alive - median post-transplant survival was 59 months (range 0-159). 72.4% of the children were transplanted with support of extracorporeal membrane oxygenation (ECMO), size-reduced donor grafts were used in 69.0%. The differences between post-transplant survival of the "non-ECMO-group" versus the "ECMO-group" (137 vs. 28 months, P=0.7) and "full size" versus "size-reduced bilateral transplants" (61 vs. 28 months, P = 0.7) were not significant, though. There were no anastomotic complications, also not in size-reduced lungs. Our results are well comparable to the international data and show excellent short- and mid-term outcomes. We advocate ECMO-bridge to be considered as a valuable treatment option to prolong time on the waiting list in highly selected patients, as well as size reduction and lobar transplants as a strong strategy to increase the donor pool and reduce donor-recipient size-mismatches. Pediatr Pulmonol. 2016;51:1222-1228. © 2016 Wiley Periodicals, Inc.

OBJECTIVES To analyse the relapse pattern and influence of second-line treatment after recurrence of malignant pleural mesothelioma (MPM) in patients who had previously undergone multimodality treatment. METHODS Between September 1999 and December 2013, 136 patients underwent macroscopic complete resection (MCR) by extrapleural pneumonectomy after induction chemotherapy for MPM. We analysed 106 patients who presented with recurrent disease until October 2014. Data were retrieved from our mesothelioma database, with additional information regarding precise localization gathered by reviewing the imaging and medical records. RESULTS The overall recurrence rate was 78% (106/136 patients). The median freedom from recurrence was 9 months after surgery [95% confidence interval (95% CI) 7-10]. Local recurrence only was observed in 33 patients (31%), distant metastases only in 27 patients (26%) and simultaneous distant and local recurrence in 46 patients (43%). Local recurrence was observed significantly less frequently in patients having received adjuvant radiotherapy (19 vs 47%, P = 0.003), but there was no significant impact on overall survival (OS) [radiation: 22 months (95% CI 19-24); no-radiation: 23 months (95% CI 18-27), P = 0.6]. The median OS was 22 months (95% CI 21-24), median post-recurrence survival (PRS) was 7 months (95% CI 5-9) and patients with local recurrence only survived significantly longer (12 months, 95% CI 8-16) compared with patients with distant recurrence only (5 months, 95% CI 2-8) or distant plus local relapse (6 months, 95% CI 3-9; P = 0.04). A total of 78 patients received a second-line therapy after tumour recurrence: chemotherapy (n = 48), local radiotherapy (n = 9), surgery (n = 10) or a combination thereof (n = 11). Patients undergoing second-line treatment survived significantly longer compared with patients not receiving therapy (P < 0.0005). The median PRS after surgery was significantly longer than that of patients receiving chemo-, radio- or chemo-radiotherapy (P = 0.04). CONCLUSIONS Local recurrence of MPM remains the most frequent type of relapse even after multimodality treatment including MCR. In the present cohort, active treatment seems beneficial to the patient since surgical excision of local tumour relapse has good long-term outcome in selected patients. Thus, second-line treatment may prolong PRS; however, these results need to be confirmed in a prospective manner.

Objectives Lung volume reduction surgery (LVRS) and lung transplantation (LTx) are the treatments of choice in selected patients with end-stage emphysema. Recently, the history of LVRS has been questioned due to reduced post-transplant survival. We aim to address this question by reviewing our experience, which is the largest single-centre series of LVRS followed by LTx. Methods We reviewed our prospectively recorded database in patients with emphysema undergoing LTx between 1993 and 2014. Preoperative workup and postoperative outcomes were compared according to previous LVRS status. The Kaplan-Meier test was used for survival analysis and compared with a log-rank test. Results One hundred and seventeen patients (66 men; mean age 56 ± 7 years) underwent LTx during the study period, 52 of whom had previous LVRS (LVRS + LTx). The mean time from LVRS to LTx was 45 ± 31 months. Patients were slightly older and had extensive smoking history in the LVRS + LTx group. Overall, in-hospital mortality was 10%, which did not differ significantly regardless of the history of LVRS (P = 0.8). The median survival for the LTx-only and LVRS + LTx groups was 86 [95% confidence interval (CI) 56-116] and 107 (95% CI 77-137) months, respectively (P = 0.6). Conclusions Previous LVRS does not negatively affect short-term and long-term outcomes following LTx in patients with end-stage emphysema. The history of LVRS should not preclude the candidacy for LTx. Considering the limited number of donors available, the LVRS option should be kept in mind for the postponement of LTx in carefully selected patients.

OBJECTIVES Overall, emphysema (EMP) is the most common indication for lung transplantation. The majority of patients present with chronic obstructive pulmonary disease (COPD) and less frequently with alpha-1 antitrypsin deficiency (A1ATD). We analysed the results of lung transplants performed for EMP in order to identify the impact of age on short- and long-term outcome. METHODS A retrospective analysis was undertaken of the 108 consecutive lung transplants for EMP performed at our institution from November 1992 to August 2013 (77 COPD, 31 A1ATD). Retransplantations were excluded. RESULTS The median age was 56 years (range 31-68). Thirty-day mortality rate was 3.7%. One- and 5-year survival rates in COPD and A1ATD recipients were comparable (P = 0.8). The 1- and 5-year survival rates for recipients aged

The use of optimal cutting temperature (OCT) medium has served to improve the long-term preservation of surgical tissue specimens. Unfortunately, the presence of polymers in OCT has been found to generate signal interference in proteomic-based techniques. Indeed the presence of OCT medium in tissue lysates precludes the analysis of activity based proteomic profiles obtained from lung adenocarcinoma (LuAdCa) resection specimens. In order to probe this question further tissue lysates were prepared from 47 lung non-neoplastic and tumour, node, metastasis (TNM) stage 1 LuAdCa resection specimens embedded with or without OCT, and data of activity based multiplex profiles of protein tyrosine kinase peptide substrates were obtained. We found that changes in overall phosphorylation level coincided with the use of OCT and subsequently developed an OCT per peptide median correcting strategy by performing median centering on the values of each peptide. Application of this post-analytical strategy not only can identify changes in kinase activity but can also assist in identifying novel targets for therapeutic intervention against LuAdCa.