• IGFBP3 inhibits lung cancer cell spheroid growth (3D proliferation). • IGFBP3 inhibits invasion by reduction of MMP activity. • Higher IGFBP3 plasma levels correlates with a less aggressive tumor. • Increased plasma levels is associated with improved overall cancer patient survival.

Despite novel immunotherapies being approved and established for the treatment of non-small cell lung cancer (NSCLC), ex vivo models predicting individual patients’ responses to immunotherapies are missing. Especially immune modulating therapies with moderate response rates urge for biomarkers and/or assays to determine individual prediction of treatment response and investigate resistance mechanisms. Here, we describe a standardized ex vivo tissue culture model to investigate individual tumor responses. NSCLC tissue cultures preserve morphological characteristics of the baseline tumor specimen for up to 12 days ex vivo and also maintain T-cell function for up to 10 days ex vivo. A semi-automated analysis of proliferating and apoptotic tumor cells was used to evaluate tissue responses to the PD-1 inhibitor nivolumab (n = 12), from which two cases could be successfully correlated to the clinical outcome. T-cell responses upon nivolumab treatment were investigated by flow cytometry and multispectral imaging. Alterations in the frequency of the Treg population and reorganization of tumor tissues could be correlated to nivolumab responsiveness ex vivo. Thus, our findings not only demonstrate the functionality of T cells in NSCLC slice cultures up to 10 days ex vivo, but also suggests this model for stratifying patients for treatment selection and to investigate in depth the tumor-associated T-cell regulation.

Iatrogenic tracheal ruptures are rare but severe complications of medical interventions. The main goal of this study was to explore prognostic factors for all-cause mortality and rupture-related (adjusted) mortality. We retrospectively analyzed patients admitted to an academic referral center over a 15-year period (2004–2018). Fifty-four patients met the inclusion criteria, of whom 36 patients underwent surgical repair and 18 patients were treated conservatively. In a 90-day follow-up, the all-cause mortality was 50%, while the adjusted mortality was 13%. Rupture length was identified as a predictor for all-cause mortality (area under the curve, 0.84; 95% confidence interval (CI) 0.74–0.94) with a cutoff rupture length of 4.5 cm (sensitivity, 0.70; specificity, 0.81). Multivariate analysis confirmed rupture length as a prognostic factor for all-cause mortality (adjusted hazard ratio (HR) 1.5; 95% CI 1.2–1.9; p = 0.001), but not for adjusted mortality (HR 1.5; 95% CI 0.97–2.3; p = 0.068), while mediastinitis predicted adjusted mortality (HR 5.8; 95% CI 1.1–31.7; p = 0.042), but not all-cause mortality (HR 1.6; 95% CI 0.7–3.5; p = 0.243). The extent of iatrogenic tracheal rupture and mediastinitis might be relevant prognostic factors for all-cause mortality and adjusted mortality, respectively.

Post-surgery liver failure is a serious complication for patients after extended partial hepatectomies (ePHx). Previously, we demonstrated in the pig model that transplantation of mesenchymal stromal cells (MSC) improved circulatory maintenance and supported multi-organ functions after 70% liver resection. Mechanisms behind the beneficial MSC effects remained unknown. Here we performed 70% liver resection in pigs with and without MSC treatment, and animals were monitored for 24 h post surgery. Gene expression profiles were determined in the lung and liver. Bioinformatics analysis predicted organ-independent MSC targets, importantly a role for thrombospondin-1 linked to transforming growth factor-β (TGF-β) and downstream signaling towards providing epithelial plasticity and epithelial-mesenchymal transition (EMT). This prediction was supported histologically and mechanistically, the latter with primary hepatocyte cell cultures. MSC attenuated the surgery-induced increase of tissue damage, of thrombospondin-1 and TGF-β, as well as of epithelial plasticity in both the liver and lung. This suggests that MSC ameliorated surgery-induced hepatocellular stress and EMT, thus supporting epithelial integrity and facilitating regeneration. MSC-derived soluble factor(s) did not directly interfere with intracellular TGF-β signaling, but inhibited thrombospondin-1 secretion from thrombocytes and non-parenchymal liver cells, therewith obviously reducing the availability of active TGF-β.

Zusammenfassung: Lungenkontusionen treten in aller Regel in Kombination mit weiteren Verletzungen auf und sprechen für eine hohe Krafteinwirkung. Vor allem bei polytraumatisierten Patienten werden Lungenkontusionen in hoher Anzahl nachgewiesen. Diese Verletzungen sind u. a. durch eine zeitliche Dynamik charakterisiert, die in der initialen Diagnostik Schwierigkeiten bereiten kann. Eine korrekte Einordnung des Verletzungsausmaßes in das Gesamtgeschehen und entsprechende diagnostische und therapeutische Schritte sind für das Erreichen einer Ausheilung essenziell. Das übergeordnete Ziel aller therapeutischen Maßnahmen ist es, dabei die Lungenfunktion bestmöglich zu erhalten und assoziierte Komplikationen wie die Entwicklung einer Pneumonie oder eines ARDS (Acute Respiratory Distress Syndrome) zu vermeiden.Die vorliegende Arbeit der interdisziplinären Arbeitsgruppe „Thoraxtrauma“ der Deutschen Gesellschaft für Unfallchirurgie (DGU) und der Deutschen Gesellschaft für Thoraxchirurgie (DGT) basiert auf einer umfangreichen Literaturrecherche zu Grundlagen, Diagnostik und Behandlung der Lungenkontusion. Es konnten ausnahmslos Arbeiten mit niedrigem Evidenzgrad eingeschlossen werden. Die Empfehlungen der vorliegenden Arbeit entsprechen einem Konsens der interdisziplinären Arbeitsgruppe.Zur initialen Diagnostik ist eine CT des Thorax mit Kontrastmittel empfohlen, das Ausmaß der Lungenkontusion korreliert mit dem Auftreten von Komplikationen. Eine konventionelle Aufnahme des Thorax kann initial die Verletzung unterbewerten, ist aber zur kurzfristigen Verlaufskontrolle geeignet.Die Therapie der Lungenkontusion ist multimodal und symptomorientiert. Insbesondere die intensivmedizinische Betreuung mit einer lungenprotektiven Beatmung und adäquaten Lagerung sind Eckpfeiler der Behandlung. Soweit es die Nebenerkrankungen und der Zustand des Patienten zulassen, sollte eine nicht invasive Beatmung erwogen werden. Abhängig von der Lungenbeteiligung und dem Patientenzustand kann ferner eine ECMO-Therapie als Ultima Ratio erwogen werden. Insbesondere diese sollte nur an spezialisierten Kliniken durchgeführt werden, weswegen eine frühzeitige Patientenzuweisung oder eine frühe Verlegung im Rahmen von Netzwerkstrukturen antizipiert werden sollte.

Resistant tumor cell populations are common after cytostatic drugs treatment. To overcome resistance mechanisms artemisinin derivatives, known for its complementary use during cancer treatement and ferroptosis induction, were investigated both as single agents and in combination with cisplatin (3 µM) in a complex organotypic tissue model of non-small cell lung cancer (NSCLC) patient samples. All substances—artemisinin (ART, 100 µM), artemether (ATM, 50 µM), artesunate (ATS, 20 µM), and dihydroartemisinin (DHA, 10 µM)—showed beneficial effects in most of the investigated patient-derived tissue cultures (PDTC). Tumor proliferation was reduced by DHA and ATS in both, standalone treatment and in combination with cisplatin, surpassing the efficacy of single cisplatin supplementation. In combination with cisplatin tumor apoptosis increased in most of lung squamous cell carcinoma (LUSC) PDTC, but not in lung adenocarcinoma (LUAD). The enzyme GPX4, inhibiting ferroptosis was up-regulated in LUAD but not in LUSC. Taken together, in the complex PDTC model system, LUSC displayed a higher sensitivity to ART derivatives, due to the lack of GPX4-mediated resistance to ferroptosis.