BACKGROUND:A quarter of a century after the National Emphysema Treatment Trial (NETT), lung volume reduction surgery (LVRS) remains an underused procedure with the notion of high mortality and morbidity, mainly recommended for upper lobe predominant heterogeneous emphysema. With advances in patient selection, minimally invasive surgery and improved recovery, this perception may be outdated. This study evaluates 5-year single-centre outcome, including patients beyond traditional NETT criteria (non-upper lobe and non-heterogeneous morphology). METHODS:This prospective study included all consecutive LVRS procedures (August 2019 to July 2024). Surgical, functional and quality of life outcomes (COPD Assessment Test (CAT) and St George's Respiratory Questionnaire (SGRQ)) were analysed at 3 and 6 months, and then annually up to 3 years. Subanalysis compared markedly versus non-markedly heterogeneous morphology and isolated versus non-isolated upper lobe disease. RESULTS:223 procedures were performed in 191 patients with baseline median (interquartile range) forced expiratory volume in 1 s (FEV1) 31% pred (27-37% pred), residual volume (RV) 219% pred (203-250% pred), 6MWD 358 (291-439) m, CAT score 22 (18-25) and SGRQ score 62 (48-71). 30-day mortality was 0.5% (n=1). Hospital stay was 7 (4-10) days; prolonged air leak occurred in 17.9% and infection in 2.2%. At 3 years (n=42/191), FEV1 improved to 38% pred (29-48% pred), RV to 173% pred (148-199% pred), CAT score to 20 (17-24) and SGRQ score to 55 (39-68), all statistically significant. Morphology was non-markedly heterogeneous in 57.6% and non-isolated upper lobe in 56%, with no significant difference in morbidity. CONCLUSIONS:This study demonstrates that LVRS performed in a specialised centre results in exceptionally low mortality and morbidity, and meaningful clinical and functional improvement, supporting broader indications beyond classical NETT criteria.

Objectives: Pulmonary metastasectomy is not a standardised procedure, with no consensus regarding the optimal extent of lung resection. This international multicentre study aimed at comparing short and long-term outcomes of anatomical versus non-anatomical pulmonary metastasectomy. Methods: Retrospective database including 1647 patients aged ≥18 years, who underwent curative intent pulmonary metastasectomy between January 2010 and December 2018 at 15 European centres. Patients who underwent pneumonectomy, previous metastasectomies, and/or suffered from extrapulmonary recurrence at the time of lung surgery were excluded. Primary endpoint was overall survival. Secondary endpoints were recurrence-free survival and 30-day morbidity. Differences between the two groups were analysed using 3:1 matching. Results: In the matched cohort, 324 patients underwent anatomical resection, and 830 patients underwent non-anatomical resection. Five-year overall survival was 62.0%. Averaged over the entire follow-up, there was no significant difference in overall survival between the two groups (HR = 1.122, 95% CI = 0.909-1.385, p = 0.283). In the early period following pulmonary metastasectomy, anatomical resections were associated with worse overall survival (HR = 1.549, 95% CI = 1.135-2.114, p = 0.006). The difference in any-site recurrence-free survival between the two groups was not significant (HR = 0.832, 95% CI = 0.690-1.002, p = 0.053). Locoregional recurrence-free survival was significantly longer after anatomical resection (HR = 0.651, 95% CI = 0.520-0.817, p < 0.001). Thirty-day morbidity was significantly higher after anatomical resection (22.2% versus 13.7% for non-anatomical resections, p = 0.001). Conclusions: In a highly selected cohort, non-anatomical resection showed comparable survival and lower morbidity compared to anatomical resections, supporting the surgical strategy of favouring limited resections whenever technically and oncologically feasible. Anatomical resections remain a valid option in selected cases with acceptable outcomes.

In the original publication [...].

OBJECTIVES:Cannabis-associated emphysema (CAE) involves bullous parenchymal destruction, often not considered for surgery due to the severe destruction and fragile tissue. It is affecting younger patients with limited smoking history, compared to typical emphysema. Given the heterogeneous pattern, lung volume reduction surgery (LVRS) may offer therapeutic benefit. This study explores the role of LVRS in patients with CAE. METHODS:CAE patients were analyzed from a prospective collected database from August 2019 until December 2024. Chest computed tomography scan, lung function (forced expiratory volume in 1 second [FEV1], residual volume [RV], quality of life [COPD Assessment Test, CAT]) and operative outcomes were measured up to one-year postintervention. RESULTS:Seven patients (median 53 years (range, 40-70), all male) with 14 joint-years (3-168) underwent 11 LVRS procedures. Four patients experienced a previous pneumothorax. The median length of stay was 6.5 days (3-14), with a chest tube duration of 5.5 days (2-14). Air leaks occurred in 7 procedures (58%) for a median of 7 days (1-10), with prolonged air leak in 3 cases (27%). There was no mortality or readmission. Relative improvement at 6 to 12 months regarding FEV1 was +44% (36-108) and RV -43% (11-62). Six-minute walking distance and CAT improved with +72 m (-28 to 152) and 11 (0-17) points, respectively. CONCLUSIONS:This preliminary single-center case series suggests that CAE may represent a suitable indication for properly performed LVRS, with favorable results attributable to its heterogeneous morphology.

PURPOSE:Adjuvant osimertinib is the standard of care for patients with resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Neoadjuvant treatment could improve surgical and long-term outcomes. METHODS:In this randomized, controlled, phase III study, patients with resectable, EGFR-mutated, stage II-IIIB NSCLC were randomly assigned (1:1:1) to receive neoadjuvant osimertinib (80 mg orally once daily for ≥9 weeks) plus platinum-based chemotherapy (once every 3 weeks for three cycles), osimertinib monotherapy (for ≥9 weeks), or placebo plus platinum-based chemotherapy (control), followed by surgical resection. Adjuvant osimertinib was offered to eligible patients after completion of surgery. The primary end point was major pathologic response (MPR) by blinded central pathology review. Event-free survival (EFS) was a secondary end point. RESULTS:Overall, 358 patients were randomly assigned to receive osimertinib plus chemotherapy (121 patients), osimertinib monotherapy (117 patients), or placebo plus chemotherapy (120 patients). Osimertinib plus chemotherapy (MPR rate 26%) and osimertinib monotherapy (25%) demonstrated statistically significant improvement in the MPR rate versus placebo plus chemotherapy (2%), with corresponding odds ratios of 19.82 (95.002% CI, 4.60 to 85.33; P < .0001) and 19.28 (99.9% CI, 1.71 to 217.39; P < .0001), respectively. With 15% data maturity, the EFS rates at 12 months were 93%, 95%, and 83% with osimertinib plus chemotherapy, osimertinib monotherapy, and placebo plus chemotherapy, respectively. In the neoadjuvant period, grade ≥3 adverse events of any cause occurred in 36%, 13%, and 33% of patients with osimertinib plus chemotherapy, osimertinib monotherapy, and placebo plus chemotherapy, respectively. No new safety concerns were identified. CONCLUSION:Neoadjuvant osimertinib with or without chemotherapy demonstrated statistically significant improvement in the MPR rate over chemotherapy alone in patients with resectable, EGFR-mutated, stage II-IIIB NSCLC.

IntroductionCD26/dipeptidyl peptidase 4 (CD26, DPP4) is a transmembrane exopeptidase that modulates tumorigenesis in different malignancies. We demonstrated before that CD26 inhibition decreases lung tumor growth in experimental models. Here, we analyzed the prognostic significance of CD26 expression and its correlation with epithelial-to-mesenchymal transition (EMT) markers in a large series of patients with non-small cell lung cancer (NSCLC).Patients and methodsNSCLC samples from operated patients were analyzed using immunohistochemistry (IHC) for the expression of CD26 and EMT markers. CD26 was scored semi-quantitatively employing tissue microarrays. Lung cancer cell lines [H460, Lewis lung carcinoma (LLC)] were tested for EMT markers, and a colony formation assay was used to test the effect of treatment with the CD26 inhibitor vildagliptin.ResultsTumor samples from 904 patients with NSCLC were analyzed. CD26 IHC expression was significantly higher in adenocarcinoma compared to squamous cell carcinoma (p < 0.0001). Patients with adenocarcinoma and CD26 expression had a better overall survival than patients without CD26 expression. The lack of CD26 expression was shown to be an independent risk factor for worse survival. CD26-expressing adenocarcinomas showed a higher expression of Vimentin and Elastin (p = 0.0027 and p < 0.0001, respectively), while E-cadherin expression was lower in this group of patients (p = 0.0021). In vitro, treatment with vildagliptin reduced the expression of Vimentin and the capacity for colony formation in H460 and LLC cell lines.Summary and conclusionThe correlation of CD26 expression in lung adenocarcinomas and better patient survival, the antiproliferative effect on tumor cells by CD26 inhibition, and an altered EMT status give rise to the hypothesis that CD26 inhibitors impact the biology and clinical course of lung adenocarcinomas.

Lung volume reduction surgery (LVRS) and bronchoscopic lung volume reduction (BLVR) are effective treatments for certain patients with severe emphysema. However, treatment access varies across centres, as not all provide both treatment options. We aimed to assess the proportion of severe COPD patients referred for BLVR that could also be eligible for LVRS. A retrospective observational study was performed of the Groningen severe COPD cohort. Strict LVRS criteria included: age ≤ 75 years, BMI between 18 and 32 kg/m2, modified Medical Research Council scale ≥ 2, amount of acute exacerbations ≤ 2, forced expiratory volume in 1 s between 20

OBJECTIVES:Lung volume reduction surgery (LVRS) is guided by strict selection criteria from the National Emphysema Treatment Trial (NETT) to minimize risk and optimize outcomes. However, emerging evidence suggests that rigid cutoffs may exclude patients who could benefit. This study aimed to identify beyond-criteria patients undergoing LVRS and compare their outcomes with standard-criteria patients. METHODS:This single-centre retrospective analysis of a prospectively maintained database included all LVRS procedures from August 2019 until November 2024. Patients were classified as beyond-criteria if they met two or more of the following: age ≥ 75 years, body mass index (BMI) < 18.5 kg/m2, forced expiratory volume in 1 second (FEV1) < 20%pred, diffusing capacity for carbon monoxide (DLCO) < 20%pred, 6-minute walk distance (6MWD) < 140 m, homogeneous emphysema, systolic pulmonary arterial pressure (sPAP) > 35 mmHg, or prior thoracic interventions. Complications (Clavien-Dindo) and functional outcomes were assessed at 3, 6, and 12 months. RESULTS:Twenty-one procedures were performed in 18 beyond-criteria patients versus 227 procedures in 191 standard-criteria patients. Among beyond-criteria patients: age ≥ 75 years (n = 3), BMI < 18.5 kg/m2 (n = 10), FEV1 < 20%pred (n = 5), DLCO < 20%pred (n = 1), 6MWD < 140 m (n = 1), homogeneous emphysema (n = 3), sPAP > 35 mmHg (n = 12), and prior thoracic intervention (n = 7). Complication rates were comparable (38% vs. 42%, P = .819 [95% CI, 0.93-1.10]), as were prolonged air leaks and hospital stay. One 30-day LVRS-related death (0.4%) occurred in the standard group. Functional and quality of life measures improved in both groups. CONCLUSIONS:Beyond-criteria patients can be considered for LVRS when guided by careful multidisciplinary evaluation, with meaningful improvement in experienced centers.

Systematic inference of enzyme activity in human tumors is key to understanding cancer progression and resistance to therapy. However, standard protein or transcript abundances are blind to the activity status of the measured enzymes, regulated, for example, by active-site amino acid mutations or post-translational protein modifications. Current methods for activity-based proteome profiling (ABPP), which combine mass spectrometry (MS) with chemical probes, quantify the fraction of enzymes that are catalytically active. Here, we describe depletion-dependent ABPP (dd-ABPP) combined with automated SWATH/DIA-MS, which simultaneously determines three molecular layers of studied enzymes: i) catalytically active enzyme fractions, ii) enzyme and background protein abundances, and iii) context-dependent enzyme-protein interactions. We demonstrate the utility of the method in advanced lung adenocarcinoma (LUAD) by monitoring nearly 4000 protein groups and 200 serine hydrolases (SHs) in tumor and adjacent tissue sections routinely collected for patient histopathology. The activity profiles of 23 SHs and the abundance of 59 proteins associated with these enzymes retrospectively classified aggressive LUAD. The molecular signature revealed accelerated lipoprotein depalmitoylation via palmitoyl(protein)hydrolase activities, further confirmed by excess palmitate and its metabolites. The approach is universal and applicable to other enzyme families with available chemical probes, providing clinicians with a biochemical rationale for tumor sample classification.

Surgical aspects and techniques of lung volume reduction surgery for severe emphysema. W. Klepetko. #ERS Journals Ltd 1999. ABSTRACT: Lung volume reduction surgery (LVRS) has become an accepted procedure for palliative treatment of diffuse, nonbullous emphysema. Single or multiple peripheral segmental wedge resections of the most destroyed areas of the lungs are performed with the use of stapling devices, in order to decrease hyperinflation and restore diaphragmatic function. Median sternotomy, videoendoscopy or anterior muscle sparing thoracotomies have been used as surgical approaches. The functional improvement after bilateral resections exceed those after a unilateral approach. LVRS has demonstrated its potential as an alternative to transplantation, and with growing experience, the indications for the procedure have been widened. In selected patients with peripheral lung cancer who have been considered unsuitable for a surgical resection, the combination of both tumour resection and LVRS has succesfully been performed. In contrast to LVRS, laser surgery of the emphysematous lung has been abandoned in most institutions. Eur Respir J 1999; 13: 919±925. Correspondence: W. Klepetko, Dept of Cardiothoracic Surgery, University of Vienna, WaÈhringerguÈrtel 18-20, A-1090 Vienna, Austria, Fax: 43 1404005642

OBJECTIVES: Lung volume reduction surgery (LVRS) is an established therapeutic option for advanced emphysema. To improve patients' safety and reduce complications, an enhanced recovery protocol (ERP) was implemented. This study aims to describe and evaluate the short-term outcome of this ERP. METHODS: This retrospective single-centre study included all consecutive LVRS patients (1 January 2017 until 15 September 2020). An ERP for LVRS was implemented and stepwise optimised from 1 August 2019, it consisted of changes in pre-, peri- and postoperative care pathways. Patients were compared before and after implementation of ERP. Primary outcome was incidence of postoperative complications (Clavien-Dindo), and secondary outcomes included chest tube duration, incidence of prolonged air leak (PAL), length of stay (LOS) and 90-day mortality. Lung function and exercise capacity were evaluated at 3 and 6 months post-LVRS. RESULTS: Seventy-six LVRS patients were included (pre-ERP: n=41, ERP: n=35). The ERP cohort presented with lower incidence of postoperative complications (42% vs 83%, P=0.0002), shorter chest tube duration (4 vs 12 days, P<0.0001) with a lower incidence of PAL (21% vs 61%, P=0.0005) and shorter LOS (6 vs 14 days, P<0.0001). No in-hospital mortality occurred in the ERP cohort versus 4 pre-ERP. Postoperative forced expiratory volume in 1 s was higher in the ERP cohort compared to pre-ERP at 3 months (1.35 vs 1.02 l) and at 6 months (1.31 vs 1.01 l). CONCLUSIONS: Implementation of ERP as part of a comprehensive reconceptualisation towards LVRS, demonstrated fewer postoperative complications, including PAL, resulting in reduced LOS. Improved short-term functional outcomes were observed at 3 and 6 months.

Generation of humanized mice using leukapheresis or human fetal liver (HFL) derived CD34+ cells.

Redirected T cells did not show persistence in the blood of tumor bearing humanized mice

PDF file, 52K, Downregulation of GLI1 target HHIP after treatment of MPM cells during 48h with HhAntag 5 μM.

While the discovery of oncogenic driver mutations has personalized the metastatic non-small cell lung cancer (NSCLC) treatment landscape with effective targeted therapies, implementation of new treatments in resectable NSCLC has been limited due to the long follow-up needed for overall survival (OS). Until recently, treatment for patients with early-stage resectable NSCLC has been limited to perioperative chemotherapy, which provides modest benefits. However, the regulatory acceptance of two surrogate endpoints for OS has allowed recent approval of both adjuvant osimertinib and atezolizumab, providing patients with new treatment options to improve outcomes. In phase 3 oncology trials, OS has historically been viewed as the gold-standard efficacy measure, but disease-free survival and event-free survival (EFS) are now validated surrogate endpoints for OS in clinical trials and should be considered when mature OS data is unavailable. Another potential surrogate endpoint in the adjuvant NSCLC setting is circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), although prospective validation is needed. For neoadjuvant targeted therapies, EFS, major pathologic response and ctDNA-based MRD are potential surrogate endpoints. To fully translate the success of the personalized treatment advances in the metastatic setting to earlier-stage disease, prospective validation studies of these potential surrogate endpoints that can accelerate the evaluation of drug efficacy are needed. A collaborative effort is also needed from all clinical and regulatory parties to collate surrogate endpoint data for large-scale validation. In this review we discuss the trends in surrogate endpoints used in oncology trials, with a focus on considerations for selecting appropriate primary endpoints in early-stage resectable EGFR-mutant NSCLC, an area of unmet need for novel treatment options.

The table shows the list of proteins correlating with TF scores as a continuous response with a FDR<0.05, by Significance Analysis of Microarrays.