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Background: Pneumothorax is a major complication following endoscopic lung volume reduction with valves with a prevalence of up to 34%. While some patients benefit from valve implantation despite pneumothorax, others are significantly impaired after lung collapse., Research Question: What are the differences in the severity grades of pneumothorax and how does that affect our clinical practice?, Study Design and Methods: This single-center retrospective study analyzed patients undergoing endoscopic valve implantation with and without post-interventional pneumothorax. Emphysema characteristics, collateral ventilation, management, and outcome of patients with pneumothorax 3 months after valve implantation were assessed. Pneumothorax was categorized as "severe pneumothorax" (chest tube insertion, prolonged air leak requiring valve removal), "moderate pneumothorax" (chest tube, no valve removal), and "mild pneumothorax" (no chest tube)., Results: Pneumothorax occurred in 102/532 patients (19%) and was significantly more common after valve placement in the upper lobes (31.3%) compared to the lower lobes (11.3%, p < 0.001). Fissure integrity was significantly higher in patients with pneumothorax (mean 96.6 ± 6.3 % vs. 93.4 ± 10.3 %, p = 0.002). Of all pneumothoraces, 30.4% were mild, 30.4% moderate, 39.2% severe. Severe pneumothorax caused multiple complications and prolonged hospitalization. Valve placement in the left upper lobe and a larger size of the target lobe were identified as risk factors for severe pneumothorax. Patients with pneumothorax developed complete lobar atelectasis in >60% as a sign of therapeutic success, but obviously only when valves could be left in place or re-implanted. However, valve re-implantation resulted in re-pneumothorax in 42.9%., Interpretation: Patients could be more individually informed about their risk of pneumothorax, which varies with target lobe location, fissure integrity and re-implantation. The poor outcome and high complication rate of severe pneumothorax calls for future research into the prediction of severe pneumothorax., (Copyright © 2024. Published by Elsevier Inc.)

Background: Immunotherapy has significantly improved overall survival in patients with pleural mesothelioma, yet this benefit does not extend to those with the epithelioid subtype. Tumor growth is believed to be influenced by the immune response. This study aimed to analyze the tumor microenvironment to gain a better understanding of its influence on tumor growth. Methods: The tumor immune cell infiltration of 188 patients with pleural mesothelioma was characterized by multiplex immunofluorescence staining for CD3+ cells (CD3+), CD4+ cells (CD3+/CD4+), CD8+ cells (CD3+/CD8+), Treg (CD3+/CD4+/CD8-/CD163-/Foxp3+), PD1 cells (PD1+), and T helper cells (CD3+/CD4+/CD8-/CD163-/FoxP3-). The distribution of specific immune cells was correlated with clinical parameters. Results: A total of 188 patients with pleural mesothelioma (135 epithelioid, 9 sarcomatoid, 44 biphasic subtypes) were analyzed. The median age was 64.8 years. Overall survival was significantly longer in the epithelioid subtype than in the non-epithelioid subtype ( p = 0.016). The presence of PD-L1 expression had a negative effect on overall survival ( p = 0.041). A high ratio of CD4+ cells to regulatory T cells was associated with a significantly longer overall survival of more than 12 months ( p = 0.015). The ratio of CD4+ cells to regulatory T cells retained its significant effect on overall survival in the multivariate analysis. Conclusions: Distinct differences in the T cell immune infiltrates in mesothelioma are strongly associated with overall survival. The tumor microenvironment could therefore serve as a source of prognostic biomarkers., Competing Interests: The authors declare no conflicts of interest.

Gender-specific differences in the diagnostics and treatment must be considered for various lung diseases. In the case of pneumothorax, in addition to differences in etiology there are also relevant differences in treatment and recurrence rates between men and women. For example, to achieve low recurrence rates catamenial pneumothorax requires interdisciplinary collaboration with gynecology. The incidence of lung cancer has equalized in recent years and in addition, various gender-specific prognostic factors have become relevant. Several meta-analyses have identified female gender as a positive prognostic factor for lung cancer, in addition to the higher prevalence of various driver mutations in women. In current trials of multimodal treatment for lung cancer, gender differences in tolerability and patient outcome are already apparent. In subgroup analyses better event-free survival was observed in women, although immune-mediated adverse events were more common in women., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Since the approval of neoadjuvant chemo-immunotherapy in Europe, treatment options for resectable stage II-III NSCLC have also significantly improved in clinical routine. Surgical excision of the tumour by anatomic lung resection still remains the most essential component of multimodal therapy. However, with the increasing use of the new treatment concepts in clinical routine, questions also arise regarding safety, adverse events and technical resectability following neoadjuvant chemo-immunotherapy. This review summarises the current data on perioperative safety following neoadjuvant chemo-immunotherapy and discusses aspects of surgical technique, the extent of resection and intraoperative challenges illustrated by clinical case reports., Competing Interests: Die Autoren erklären, dass sie innerhalb der vergangenen 3 Jahre Vortragshonorare bzw. Forschungsförderung von MSD, BMS, AstraZeneca und Intuitive Surgical erhalten und als Berater tätig waren., (Thieme. All rights reserved.)

PET using 68 Ga-labeled fibroblast activation protein (FAP) inhibitors (FAPIs) holds high potential for diagnostic imaging of various malignancies, including lung cancer (LC). However, 18 F-FDG PET is still the clinical gold standard for LC imaging. Several subtypes of LC, especially lepidic LC, are frequently 18 F-FDG PET-negative, which markedly hampers the assessment of single pulmonary lesions suggestive of LC. Here, we evaluated the diagnostic potential of static and dynamic 68 Ga-FAPI-46 PET in the 18 F-FDG-negative pulmonary lesions of 19 patients who underwent surgery or biopsy for histologic diagnosis after PET imaging. For target validation, FAP expression in lepidic LC was confirmed by FAP immunohistochemistry. Methods: Hematoxylin and eosin staining and FAP immunohistochemistry of 24 tissue sections of lepidic LC from the local tissue bank were performed and analyzed visually. Clinically, 19 patients underwent static and dynamic 68 Ga-FAPI-46 PET in addition to 18 F-FDG PET based on individual clinical indications. Static PET data of both examinations were analyzed by determining SUV max , SUV mean , and tumor-to-background ratio (TBR) against the blood pool, as well as relative parameters ( 68 Ga-FAPI-46 in relation to 18 F-FDG), of histologically confirmed LC and benign lesions. Time-activity curves and dynamic parameters (time to peak, slope, k 1 , k 2 , k 3 , and k 4 ) were extracted from dynamic 68 F-FDG ratios for all parameters than did benign pulmonary lesions. Dynamic imaging analysis revealed differential time-activity curves for LC and benign pulmonary lesions: initially increasing time-activity curves with a decent slope were typical of LC, and steadily decreasing time-activity curve indicated benign pulmonary lesions, as was reflected by a significantly increased time to peak and significantly smaller absolute values of the slope for LC. Relative Results: FAP immunohistochemistry confirmed the presence of strongly FAP-positive cancer-associated fibroblasts in lepidic LC. LC showed markedly elevated 68 F-FDG ratios regarding SUV 68 Ga-FAPI-46-to- 18 F-FDG ratios for all parameters than did benign pulmonary lesions. Dynamic imaging analysis revealed differential time-activity curves for LC and benign pulmonary lesions: initially increasing time-activity curves with a decent slope were typical of LC, and steadily decreasing time-activity curve indicated benign pulmonary lesions, as was reflected by a significantly increased time to peak and significantly smaller absolute values of the slope for LC. Relative 68 F-FDG-negative pulmonary lesions and may optimize patient stratification in this clinical setting.18 F-FDG ratios regarding SUV max and TBR showed the highest sensitivity and specificity for the discrimination of LC from benign pulmonary lesions. Conclusion: 68 Ga-FAPI-46 PET is a powerful new tool for the assessment of single 18 F-FDG-negative pulmonary lesions and may optimize patient stratification in this clinical setting., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The role of cytoreductive surgery for epithelioid pleural mesothelioma within a multimodal treatment approach remains controversial. Carefully selected patients benefit from cytoreductive surgery and adjuvant chemotherapy, but there is no established biomarker to predict tumor recurrence or progression during the course of the disease. The aim of this study was to identify potential biomarkers to predict therapeutic response in terms of progression-free survival., Methods: Between 03/2014 and 08/2022, preoperative blood samples were collected from 76 patients with epithelioid pleural mesothelioma who underwent cytoreductive surgery as part of a multimodal treatment approach. Identification of potential biomarkers was performed by determination of mesothelin and calretinin, as well as specific long non-coding RNAs and microRNAs. Receiver operating characteristic analysis, Kaplan-Meier survival analysis, and Cox regression were used to assess the association between biomarker concentrations and patient recurrence status and survival., Results: MALAT1, GAS5, and calretinin showed statistically significant increased biomarker levels in patients with recurrence in contrast to recurrence-free patients after surgical treatment (p < 0.0001, p = 0.0190, and p = 0.0068, respectively). The combination of the three biomarkers resulted in a sensitivity of 68 % and a specificity of 89 %., Conclusion: MALAT1, GAS5, and calretinin could be potential biomarkers for the prediction of tumor recurrence, improving the benefit from multimodal treatment including cytoreductive surgery., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The IPA has supplied DLD Diagnostika GmbH with the antibodies for the production of the Calretinin ELISA kits. In return, the IPA has received Calretinin ELISA kits at a reduced price and may benefit from future sales of the kits. Otherwise, the individual authors declare any competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Malignant primary tracheal tumours are rare. The most common histological subtypes are squamous cell carcinoma and adenoid cystic carcinoma. These two entities have different prognoses and growth patterns. Tracheobronchoscopy and thoracic sectional imaging are standard diagnostic tools for tumour staging and local evaluation. Complete surgical resection of the affected tracheal segment is the treatment of choice for limited disease without distant metastases. Incomplete gross tumour resection with additional irradiation is an acceptable therapeutic option for adenoid cystic carcinoma. Interventional endoscopy with tumour debulking or tracheal stenting and/or definitive mediastinal radiotherapy are treatment alternatives in either a locally advanced or palliative setting., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Approximately one half of patients with non-small cell lung cancer (NSCLC) are diagnosed at resectable tumor stages (I-IIIA), which can potentially be curatively treated. In the early tumor stages (tumor diameter ≤2 cm) sublobar resection (segmentectomy or atypical wedge resection) leads to a 5‑year long-term survival comparable to lobectomy. The use of immunotherapy, especially within the framework of neoadjuvant treatment, is anticipated to change the surgical treatment of NSCLC in the future. With the introduction of lung cancer screening for certain risk groups in Germany planned for 2024, lung tumors can be expected to be diagnosed at earlier stages and more frequently curatively treated. This article provides an overview of the potential impact of lung cancer screening, modern minimally invasive surgical techniques and neoadjuvant treatment concepts for the surgical treatment of NSCLC., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: The tumoral immune milieu plays a crucial role for the development of non-small-cell lung cancer (NSCLC) and may influence individual prognosis. We analyzed the predictive role of immune cell infiltrates after curative lung cancer surgery., Materials and Methods: The tumoral immune-cell infiltrate from 174 patients with pN1 NSCLC and adjuvant chemotherapy was characterized using immunofluorescence staining. The density and distribution of specific immune cells in tumor center (TU), invasive front (IF) and normal tissue (NORM) were correlated with clinical parameters and survival data., Results: Tumor specific survival (TSS) of all patients was 69.9% at 5 years. The density of tumor infiltrating lymphocytes (TIL) was higher in TU and IF than in NORM. High TIL density in TU (low vs. high: 62.0% vs. 86.7%; p = .011) and the presence of cytotoxic T-Lymphocytes (CTLs) in TU and IF were associated with improved TSS (positive vs. negative: 90.6% vs. 64.7% p = .024). High TIL-density correlated with programmed death-ligand 1 expression levels ≥50% (p < .001). Multivariate analysis identified accumulation of TIL (p = .016) and low Treg density (p = .003) in TU as negative prognostic predictors in squamous cell carcinoma (p = .025), whereas M1-like tumor- associated macrophages (p = .019) and high programmed death-ligand 1 status (p = .038) were associated with better survival in adenocarcinoma., Conclusion: The assessment of specific intratumoral immune cells may serve as a prognostic predictor in pN1 NSCLC. However differences were observed related to adenocarcinoma or squamous cell carcinoma histology. Prospective assessment of the immune-cell infiltrate and further clarification of its prognostic relevance could assist patient selection for upcoming perioperative immunotherapies., Competing Interests: Disclosure Thomas Muley has received grants/contracts from Roche Diagnostics and Oncohost outside the submitted work. Petros Christopoulos has received research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Novartis, Roche, and Takeda, speaker's honoraria from AstraZeneca, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. Hauke Winter has received received payment (lectures, presentations, speaker fee, manuscript writing, educational events) from MSD, AstraZeneca, Intuitive, Medtronic, Roche; expert testimony from Intuitive; support for attending meetings/travel from Roche, Intuitive, MSD and participation on Data Safety Monitoring/Advisory Board for AstraZeneca and Intuitive; all outside the submitted work. Florian Eichhorn, Andreas Weigert, Rajender Nandigama, Laura Klotz, Jochen Wilhelm, Mark Kriegsmann, Michael Allgäuer, Rajkumar Savai and Martin Eichhorn declare that they have no known conflict of interest or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: First-line pembrolizumab alone, as approved for PD-L1 ≥50%, or with chemotherapy was analyzed in older non-small-cell lung cancer (NSCLC) patients, for whom evidence is scarce., Materials and Methods: A total of 156 consecutive ≥70 year-old patients treated between January 2016 and May 2021 were retrospectively analyzed. Tumor progression was verified through radiologic review, while toxicity was captured from records., Results: Pembrolizumab plus chemotherapy (n = 95) caused higher rates of adverse events (91% vs. 51%, P < .001), treatment discontinuation (37% vs. 21%, P = .034), and hospitalization (56% vs. 23%, P < .001), but similar rates of immune-related adverse events (irAEs, mean 35%, P = .998) compared to pembrolizumab monotherapy (n = 61). Progression-free (PFS) and overall survival (OS) were similar between the 2 groups (7 vs. 8 months, and 16 vs. 14 months in median, P > .25). Occurrence of irAEs was associated with longer survival in a 12-week landmark analysis (median PFS 11 vs. 5 months, hazard ratio [HR] 0.51, P = .001; median OS 33 vs. 10 months, HR 0.46, P < .001), but occurrence of other AEs not (both P > .35). A worse ECOG performance status (PS) ≥2, presence of brain metastases at diagnosis, squamous histology and lack of tumor PD-L1 expression were independent predictors of shorter PFS and OS in multivariable analysis (HR 1.6-3.9 for PFS and OS, all P < .05)., Conclusion: Chemoimmunotherapy increases the rate of adverse events and hospitalization without prolonging PFS or OS in newly diagnosed NSCLC patients aged 70 years or older compared to pembrolizumab monotherapy. ECOG PS 2, presence of brain metastases at diagnosis, squamous histology and PD-L1 negativity are associated with poor outcome., Competing Interests: Conflict of Interest MB: none. JK: speaker's honoraria from BMS, AstraZeneca and Pfizer, travel grants from Takeda, advisory board honoraria from Takeda, Roche and AstraZeneca. RS: research funding from BMS, speaker's honoraria from AstraZeneca, Roche, Novartis. FB: research funding from BMS and travel grants from BMS and MSD. FE: speaker's honoraria from MSD, BMS, Novartis and AstraZeneca, consulting fees from BMS. SL: commercial research grants from BerGenBio AS, BMS, Eli Lilly and Roche Pharma, honoraria from the Speakers Bureau and/or is a consultant/advisory board member and/or received travel grants of BerGenBio AS, BMS, Boehringer Ingelheim, Eli Lilly, Roche Pharma, Medac GmbH, Astra Zeneca, Chugai, Novartis, Abbvie, MDS and Sanofi Aventis. AS: advisory board honoraria from BMS, AstraZeneca, ThermoFisher, Novartis, speaker's honoraria from BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, MSD, Roche, and research funding from Chugai. CPH: consultation, lecture and other fees from Novartis, Basilea, Bayer, Grifols, Boehringer, Pierre Fabre, Covidien, Siemens, Chiesi, Intermune, MEDA Pharma, Bracco, Pfizer, MSD, Roche, Lilly, AstraZeneca, Schering-Plough, Essex, Gilead, MeVis, Fresenius, Astellas as well as ownership of GSK stocks FJH: advisory board fees and honoraria from Lilly, Roche, AstraZeneca, Novartis, Boehringer, Chiesi, Teva, Pulmonx BTG and Olympus as well as research funding from Lilly, Roche, AstraZeneca, Novartis, Boehringer, Chiesi and Teva. MT: advisory board honoraria from Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer, speaker's honoraria from Lilly, MSD, Takeda, research funding from AstraZeneca, BMS, Celgene, Novartis, Roche and travel grants from BMS, MSD, Novartis, Boehringer. PC: research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Takeda, and advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, Chugai, Janssen, Novartis, Pfizer, Roche, Takeda, Thermo Fisher., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The interest in non-intubated video-assisted thoracic surgery (NIVATS) has risen over the last decade and numerous terms have been used to describe this technique. They all have in common, that the surgical procedure is performed in a spontaneously breathing patient under locoregional anaesthesia in combination with intravenous sedation but have also been performed on awake patients without sedation. Evidence has been generated favouring NIVATS compared to one-lung-ventilation under general anaesthesia., Main Body: We want to give an overview of how NIVATS is performed, and which different techniques are possible. We discuss advantages such as shorter length of hospital stay or (relative) contraindications like airway difficulties. Technical aspects, for instance intraoperative handling of the vagus nerve, are considered from a thoracic surgeon's point of view. Furthermore, special attention is paid to the cohort of patients with interstitial lung diseases, who seem to benefit from NIVATS due to the avoidance of positive pressure ventilation. Whenever a new technique is introduced, it must prove noninferiority to the state of the art. Under this aspect current literature on NIVATS for lung cancer surgery has been reviewed., Conclusion: NIVATS technique may safely be applied to minor, moderate, and major thoracic procedures and is appropriate for a selected group of patients, especially in interstitial lung disease. However, prospective studies are urgently needed., (© 2022. The Author(s).)

Honeycomb-based, modular composites with a relative density of 0.3948 and a slenderness ratio L ges /t of 6.48 were fabricated on PZT building blocks connected with a PZT-filled phenyl silicone resin. The macro- and micro-structure, phase composition, and the interface between the two materials were analyzed by SEM and image analysis techniques. The mechanical in-plane strain response was determined with uniaxial compression tests and the transversal piezoelectric strain response was determined by applying an electric field. These deformations were analyzed by a 2D digital image correlation analysis to calculate the mechanical strain amplification of monolithic and composite PZT lattice structures. Compared to bulk PZT, the piezoelectric strain amplification in the Y-direction | a y piezo | was higher by a factor of 69 for the composite and by a factor of 12 for the monolithic cellular PZT lattice, when it was assumed that the ratio of the deformation of the bulk material to bulk material was 1. The mechanical amplification of the composite lattices increased up to 73 and that of the cellular PZT lattices decreased to 12. Special focus was given to the fracture behavior and the interface of the PZT/PZT-filled phenyl silicone resin interface.

Background: The exact role and type of surgery for malignant pleural mesothelioma (MPM) remains controversial. This study aimed at analyzing a 20-year single center perioperative experience in MPM surgery at our high-volume thoracic surgery center and comparing the overall survival after trimodal extrapleural pneumonectomy (EPP) and extended pleurectomy and decortication combined with hyperthermic intrathoracic chemoperfusion (EPD/HITOC) and adjuvant chemotherapy with that after chemotherapy (CTx) alone., Methods: Patients with epithelioid MPM treated with neoadjuvant chemotherapy, EPP and adjuvant radiotherapy within a trimodal concept or EPD/HITOC in combination with adjuvant chemotherapy between 2001 and 2018 were included in this retrospective analysis. Surgical cohorts were compared to patients treated with standard chemotherapy., Results: Overall, 182 patients (69 EPP, 57 EPD/HITOC, 56 CTx) were analyzed. Due to occupational exposure to asbestos for most of the patients, 154 patients (84.6%) were male. The patients in the surgical cohorts were significantly younger than those in the CTx cohort. There was no significant difference between the proportion of patient age and side. The median overall survival of the EPD/HITOC cohort with 38.1 months was significantly longer than that of the EPP and CTx cohorts (24.0 and 15.8 months). Better survival was significantly associated with an ECOG 0 performance status, age below 70 years, and negative lymph node status. In the multivariate analysis, EPD/HITOC was significantly associated with improved overall survival. Perioperative morbidity was lower in the EPD/HITOC group than in the EPP cohort., Conclusions: EPD/HITOC is feasible and safe for localized epithelioid pleural mesothelioma. Changing the surgical approach to a less radical lung-sparing technique may improve overall survival compared to trimodal EPP., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-199/coif). RS has received honoraria for lectures from Roche and AstraZeneca and an institutional grant from BMS outside the submitted work. FE received consulting fees from the Roche Pharma AG outside the submitted work. CG received consulting fees from Bristol Myers Squibb and speakers honoraria from Astra Zeneca, all outside the submitted work. PC has received research funding from AstraZeneca, Novartis, Roche, and Takeda, speaker’s honoraria from AstraZeneca, Novartis, Roche, Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Gilead, Novartis, Takeda, and personal fees for participating to advisory boards from Boehringer Ingelheim, Chugai, Pfizer and Roche, all outside the submitted work. MT received institutional grants from Astra Zeneca, Bristol-Myers Squibb, Merck, Roche, and Takeda, speakers honoraria from AbbVie, AstraZeneca, Beigene, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, MSD, Novartis, Pfizer, Sanofi, Roche, and Takeda as well as support for attendance of meetings from AstraZeneca, Bristol-Myers Squibb, Janssen Oncology, MSD, Pfizer, Roche, and Takeda. For participation in the advisory board, MT received honoraria from AbbVie, AstraZeneca, Beigene, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, MSD, Novartis, Pfizer, Sanofi, Roche, and Takeda, all outside the submitted work. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Introduction: PD-(L)1 inhibitors (IO) have improved the prognosis of non-small-cell lung cancer (NSCLC), but more reliable predictors of efficacy and immune-related adverse events (irAE) are urgently needed. Cytokines are important effector molecules of the immune system, whose potential clinical utility as biomarkers remains unclear., Methods: Serum samples from patients with advanced NSCLC receiving IO either alone in the first (1L, n=46) and subsequent lines (n=50), or combined with chemotherapy (ICT, n=108) were analyzed along with age-matched healthy controls (n=15) at baseline, after 1 and 4 therapy cycles, and at disease progression (PD). Patients were stratified in rapid progressors (RP, progression-free survival [PFS] <120 days), and long-term responders (LR, PFS >200 days). Cytometric bead arrays were used for high-throughput quantification of 20 cytokines and other promising serum markers based on extensive search of the current literature., Results: Untreated NSCLC patients had increased levels of various cytokines and chemokines, like IL-6, IL-8, IL-10, CCL5, G-CSF, ICAM-1, TNF-RI and VEGF (fold change [FC]=1.4-261, p=0.026-9x10 -7 ) compared to age-matched controls, many of which fell under ICT (FC=0.2-0.6, p=0.014-0.002), but not under IO monotherapy. Lower baseline levels of TNF-RI were associated with longer PFS (hazard ratio [HR]= 0.42-0.54; p=0.014-0.009) and overall survival (HR=0.28-0.34, p=0.004-0.001) after both ICT and IO monotherapy. Development of irAE was associated with higher baseline levels of several cytokines, in particular of IL-1β and angiogenin (FC=7-9, p=0.009-0.0002). In contrast, changes under treatment were very subtle, there were no serum correlates of radiologic PD, and no association between dynamic changes in cytokine concentrations and clinical outcome. No relationship was noted between the patients' serologic CMV status and serum cytokine levels., Conclusions: Untreated NSCLC is characterized by increased blood levels of several pro-inflammatory and angiogenic effectors, which decrease under ICT. Baseline serum cytokine levels could be exploited for improved prediction of subsequent IO benefit (in particular TNF-RI) and development of irAE ( e.g. IL-1β or angiogenin), but they are not suitable for longitudinal disease monitoring. The potential utility of IL-1/IL-1β inhibitors in the management and/or prevention of irAE in NSCLC warrants investigation., Competing Interests: Author KB received consultancy and/or speaker fees and/or travel reimbursements from Abbvie, Bristol Myers Squibb BMS, Gilead/Galapagos, Janssen, Merck Sharp & Dohme MSD, Mundipharma, Novartis, Pfizer, Roche, Viatris, UCB, as well as scientific support from the Medical Faculty of University of Heidelberg, Rheumaliga Baden-Württemberg e.V., AbbVie, and Novartis. Author FE received personal fees from Roche and BMS; DK: advisory board and speaker’s honoraria from AstraZeneca, BMS, Pfizer. Author AS received advisory board honoraria from BMS, AstraZeneca, ThermoFisher, Novartis, speaker’s honoraria from BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, MSD, Roche, and research funding from Chugai. Author HoS received research grants and personal fees from Roche Sequencing Solutions, outside the submitted work. Author MT received advisory board honoraria from Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer, speaker’s honoraria from Lilly, MSD, Takeda, research funding from AstraZeneca, BMS, Celgene, Novartis, Roche and travel grants from BMS, MSD, Novartis, Boehringer. Author PC received research funding from Amgen, AstraZeneca, Merck, Novartis, Roche, Takeda, and advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schindler, Lusky, Daniello, Elshiaty, Gaissmaier, Benesova, Souto-Carneiro, Angeles, Janke, Eichhorn, Kazdal, Schneider, Liersch, Klemm, Schnitzler, Stenzinger, Sültmann, Thomas and Christopoulos.)

Background: EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce., Patients and Methods: We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases., Results: Platinum doublets and chemoimmunotherapy showed similar response rates (20-25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p < 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p < 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3-6.1, p < 0.01), and shorter OS for patients receiving both treatments (p < 0.05). More tumour CD8 + and less Th1 cells were associated with longer OS independent of brain and TP53 status (p < 0.01). No difference in outcome was noted according to the ex20ins site and use of pemetrexed (vs. other cytotoxics) or bevacizumab. Long-lasting responses (>1 year) occasionally occurred under EGFR inhibitors for both 'near-' and 'far-loop' variants., Conclusions: Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20-25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival., Competing Interests: Conflict of interest statement PC: research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Takeda, and advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, Takeda. JR: lecture fees from AstraZeneca, Boehringer Ingelheim. FCS: research funding from Roche; non-financial support from Lilly; personal fees from Takeda, and Pfizer, outside the submitted work. BH: advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, BMS, MSD, Roche, Pfizer. JK: research funding from AstraZeneca and Celgene. MJ: speaker's honoraria from Roche, Boehringer, and travel grants from Daiichi Sankyo. DK: advisory boards/speakers honoraria from AstraZeneca, BMS, Boehringer Ingelheim, GSK, MSD, Novartis, Pfizer, Roche, Takeda. FE: speaker's honoraria from Roche. FB: research funding from AstraZeneca, BMS and Roche, and travel grants from BMS and MSD. RS: research funding from BMS, and speaker's honoraria from AstraZeneca and Roche. AT: research funding from BMS. MW: research funding from Roche; Personal fees from Roche, AstraZeneca, Boehringer, Kite, Novartis, Merck, BMS, Heidelberg Pharma; Non-financial support from AstraZeneca, BMS, Glenmark; outside the submitted work. SL: advisory board, speaker's honoraria and travel support from BerGenBio, Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AstraZeneca, Sanofi, as well as research funding from Roche, BMS, BerGenBio. WB: consulting fees from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Pfizer, Roche, Sanofi, honoraria for lectures from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Pfizer, Roche, Sanofi. Travel grants from AstraZeneca, Boehringer Ingelheim, MSD, Roche. CS: advisory board honoraria from AstraZeneca, Boehringer Ingelheim, BMS, MSD, Novartis, Roche, Pfizer, Takeda. Speaker's honoraria from AstraZeneca, Boehringer, Lilly, Roche, MSD, Takeda. DM: advisory board/lecture fees from AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Roche, Sanofi and Takeda (no personal honoraria) NF: advisory board/lecture fees from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Pfizer, Roche, MSD, Takeda. JK: advisory board member without receiving any personal fees for Roche Pharma, Boehringer Ingelheim, BMS, MSD, Amgen, Lilly and Takeda. MR: advisory board/lecture fees from Amgen, AstraZeneca, BMS, Boehringer, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Samsung. FG: grants and personal fees from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche, Takeda, as well as personal fees from AbbVie, Tesaro/GSK, Blueprint Medicines, Amgen. CG: advisory board/lecture fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Takeda, MSD, Novartis, Pfizer, Roche, AbbVie, Tesaro/GSK and Blueprints Medicines. AS: advisory board honoraria from BMS, AstraZeneca, ThermoFisher, Novartis, speaker's honoraria from BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, MSD, Roche, and research funding from Chugai and BMS. MT: advisory board honoraria from Novartis, Eli Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer Ingelheim, Pfizer, speaker's honoraria from Eli Lilly, MSD, Takeda, Pfizer, research funding from AstraZeneca, BMS, Celgene, Novartis, Roche, Takeda, and travel grants from BMS, MSD, Novartis, Boehringer. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Surgical lung biopsy (SLB) is recommended for patients with nonclassified interstitial lung disease (nILD) if high resolution computed tomography and/or transbronchial lung biopsy did not achieve a definitive diagnosis. Current literature suggests better patient tolerability and less postoperative complications if surgery is performed under spontaneous ventilation., Objectives: We conducted a propensity score matching (PSM) analysis of our nILD patients undergoing SLB under spontaneous ventilation or general anesthesia to investigate postprocedural AE-ILD, 30-/90-day mortality and perioperative variables in two academic high-volume centers (Hannover, Heidelberg)., Methods: All patients undergoing SLB for nILD under general anesthesia (GAVATS) and spontaneous ventilation (NIVATS) at both centers from February 2013 until April 2021 were analyzed retrospectively. Data of 132 patients were used for PSM resulting in 40 pairs., Results: There was one death in the NIVATS group 60 days after SLB and one AE-ILD in each cohort. Chest tube indwelling time, chest tube total effusion, length of hospital stay, and operative time were all in favor of NIVATS., Conclusions: In our PSM analysis, NIVATS is associated with faster postprocedural recovery. However, a reduction in postoperative AE-ILD or 30-/90-day mortality was not observed., (© 2022 S. Karger AG, Basel.)