Objectives: Extracorporeal life support is increasingly used to bridge deteriorating candidates to lung transplantation. Nevertheless, only few systematic reports with a limited number of patients exist describing this practice and its changes over time. Methods:We retrospectively reviewed our institutional database and performed an era analysis to identify trends over time and risk factors for mortality. After applying propensity score matching, outcomes of bridged patients were compared with those of standard lung transplantation recipients.Results: Extracorporeal life support was used in 120 patients as an intention to bridge to lung transplantation. Eleven patients (9.2%) were bridged between 1998 and 2004, 39 patients (32.5%) were bridged between 2005 and 2010, and 70 patients were bridged (58.3%) between 2010 and 2017. In the first era, the main bridging modality was venoarterial-extracorporeal membrane oxygenation (n ¼ 10, 90.9%), whereas venovenous devices were primarily used in later eras (second era: n ¼ 18, 46.2%; third era: n ¼ 39, 55.8%). In the second and third eras, 9 patients (23.1%) and 24 patients (34.3%) could be bridged awake. Short-term outcome was poor in the first era, with only 36.4% of patients discharged alive but improved in later eras (53.8% and 77.1%; P ¼ .002). Extracorporeal life support-bridged patients showed an impaired short-term outcome compared with standard recipients. However, survival conditional on 90 days did not differ among the groups (P ¼ .178). In univariate and multivariate analyses, awake extracorporeal life support was protective for survival, whereas acute retransplantation was a risk factor for mortality.Conclusions: Over the past 2 decades, the role of extracorporeal life support bridging evolved from an acute rescue therapy to a semi-elective procedure. Stratified outcome analysis revealed that extracorporeal life support bridging yielded similar long-term survival compared with nonbridged patients.

Metastatic melanoma is hallmarked by its ability of phenotype switching to more slowly proliferating, but highly invasive cells. Here, we tested the impact of signal transducer and activator of transcription 3 (STAT3) on melanoma progression in association with melanocyte inducing transcription factor (MITF) expression levels. We established a mouse melanoma model for deleting Stat3 in melanocytes with specific expression of human hyperactive NRAS Q61K in an Ink4a deficient background, two frequent driver mutations in human melanoma. Mice devoid of Stat3 showed early disease onset with higher proliferation in primary tumors, but displayed significantly diminished lung, brain and liver metastases. Whole genome expression profiling of tumor-derived cells also showed a reduced invasion phenotype, which was further corroborated by 3D melanoma model analysis. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3-induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that CEBPa/b binding to the MITF enhancer region silenced the MITF locus. Finally, by classification of patient-derived melanoma samples, we show that STAT3 and MITF act antagonistically and hence contribute differentially to melanoma progression. We conclude that STAT3 is a driver of the metastatic process in melanoma and able to antagonize MITF via direct induction of CEBP family member transcription.

Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3α and STAT3β. Although truncated STAT3β was originally postulated to act as a dominant-negative form of STAT3α, it has been shown to have various STAT3α-independent regulatory functions. Recently, STAT3β gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3β in AML remains elusive. Therefore, we analyzed the STAT3β/α messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3β/α mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3β in AML, we engineered a transgenic mouse allowing for balanced Stat3β expression. Transgenic Stat3β expression resulted in decelerated disease progression and extended survival in PTEN- and MLL-AF9–dependent AML mouse models. Our findings further suggest that the antitumorigenic function of STAT3β depends on the tumor-intrinsic regulation of a small set of significantly up- and downregulated genes, identified via RNA sequencing. In conclusion, we demonstrate that STAT3β plays an essential tumor-suppressive role in AML.