Fast proliferating and slowly migrating non-small cell lung cancer cells are vulnerable to decitabine and retinoic acid combinatorial treatment.

Non-small cell lung cancer (NSCLC) patients are often elderly or unfit and thus cannot tolerate standard aggressive therapy regimes. In our study, we test the efficacy of the DNA-hypomethylating agent decitabine (DAC) in combination with all-trans retinoic acid (ATRA), which has been shown to possess little systemic adverse effects. Screening a broad panel of 56 NSCLC cell lines uncovered a decrease in cell viability after the combination treatment in 77% of the cell lines. Transcriptomics, proteomics, proliferation and migration profiling revealed that fast proliferating and slowly migrating cell lines were more sensitive to the drug combination. The comparison of mutational profiles found oncogenic KRAS mutations only in sensitive cells. Additionally, different cell lines showed a heterogeneous gene expression response to the treatment pointing to diverse mechanisms of action. Silencing KRAS, RIG-I or RARB partially reversed the sensitivity of KRAS-mutant NCI-H460 cells. To study resistance, we generated two NCI-H460 cell populations resistant to ATRA and DAC, which migrated faster and proliferated slower than the parental sensitive cells and showed signs of senescence. In summary, this comprehensive dataset uncovers a broad sensitivity of NSCLC cells to the combinatorial treatment with DAC and ATRA and indicates that migration and proliferation capacities correlate with and could thus serve as determinants for drug sensitivity in NSCLC.

Endoscopic Lung Volume Reduction Prior to Lung Transplantation Does Not Increase Postoperative Pulmonary Complications.

INTRODUCTION: Lung transplantation (LTx) remains the only therapeutic option for selected patients with end-stage lung disease. In comparison to surgical lung volume reduction, few data exist on the risks and benefits of pretransplant endoscopic lung volume reduction (eLVR). Here, we investigate the risk of postoperative pulmonary complications (PPCs) after LTx in patients with emphysematous lung disease bridged with eLVR until transplantation. METHODS: Eighty-two patients with emphysematous lung disease who underwent double-LTx (DLTx) were included and retrospectively evaluated. Statistical analysis was performed using SPSS and GraphPad Prism software. RESULTS: 28/82 patients underwent eLVR prior to DLTx. eLVR patients spent comparable time on the waitlist; however, they were older at the time of DLTx (median 60 vs. 58 years, p = 0.02). Both groups showed comparable 90-day (92%) and long-term survival (eLVR 1-/5-/10-year survival: 92/88/77%, vs. control: 89/77/67%, p = 0.5). The odds for PPCs were similar in patients with and without eLVR (OR 0.7; 95% CI: 0.3-1.7), as well as major perioperative surgical and cardiovascular complications. In the entire cohort, we found ≥1 PPC to be a risk factor for death within 90 days (OR 9.7, 95% CI: 1.3-110). Among the PPCs, pneumonia (HR 4.6 95% CI: 1.1-14.9, p = 0.02) and ARDS (HR 11.2 95% CI: 1.6-229.2, p = 0.04) were identified as independent risk factors for reduced long-term survival. CONCLUSIONS: eLVR does not increase the risk for PPCs, surgical complications, or reduced survival after LTx in patients with emphysematous lung disease and can serve as a bridge to LTx.

Risk Factors for Postoperative Pulmonary Complications Leading to Increased Morbidity and Mortality in Patients Undergoing Thoracic Surgery for Pleural Empyema.

OBJECTIVES: Surgery for pleural empyema carries a high burden of morbidity and mortality. The authors investigated the incidence of postoperative pulmonary complications (PPCs) and their effects on perioperative morbidity and mortality. Patient-specific, preoperative, procedural, and postoperative risk factors for PPCs were analyzed. DESIGN: Retrospective observational study. SETTING: A single, large university hospital. PARTICIPANTS: A total of 250 adult patients were included who underwent thoracic surgery for pleural empyema between January 2017 and December 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 250 patients with pleural empyema underwent thoracic surgery by video-assisted thoracoscopic surgery (49%; n = 122) or open thoracotomy (51%; n = 128). A proportion (42% [105]) of patients had ≥1 PPCs; 28% (n = 70) had to undergo resurgery; and 10% (n = 25) were re-admitted unexpectedly to the ICU. Preoperative respiratory failure (odds ratio [OR]: 5.8, 95% CI: 2.4-13.1), general anesthesia without regional analgesia techniques (OR: 2.9, 95% CI: 1.4-5.8), open thoracotomy and subsequent resurgery (OR: 3.9, 95% CI 1.5-9.9), surgery outside the regular working hours (OR: 3.1, 95% CI 1.2-8.2), and postoperative sepsis (OR: 2.6, 95% CI 1.1-6.8) were identified as independent risk factors for PPCs. Postoperative pulmonary complications were independent factors for unplanned intensive care unit admission (OR: 10.5, 95% CI 2.1-51 for >1 PPC), death within 360 days (OR: 4.5, 95% CI 2.2-12.3 for ≥2 PPCs), and death within 30 days for ≥1 PPCs (OR: 1.2, 95% CI 1.1-1.3). CONCLUSIONS: The incidence of PPCs is a significant risk factor for morbidity and mortality after surgery for pleural empyema. Targeting the risk factors identified in this study could improve patient outcomes.

Independent risk factors for an increased incidence of thromboembolism after lung transplantation.

BACKGROUND: Thromboembolism (TE) after lung transplantation (LTX) is associated with increased morbidity and mortality. The aim of this study is to analyze the incidence and outcome of venous and arterial thromboembolic complications and to identify independent risk factors. PATIENTS AND METHODS: We retrospectively analyzed the medical records of 221 patients who underwent LTX at our institution between 2002 and 2021. Statistical analysis was performed using SPSS and GraphPad software. RESULTS: 74 LTX recipients (33%) developed TE. The 30-days incidence and 12-months incidence were 12% and 23%, respectively. Nearly half of the patients (48%) developed pulmonary embolism, 10% ischemic stroke. Arterial hypertension (p = 0.006), a body mass index (BMI) > 30 (p = 0.006) and diabetes mellitus (p = 0.041) were independent predictors for TE. Moreover, a BMI of > 25 at the time of transplantation was associated with an increased risk for TE (43% vs. 32%, p = 0.035). At the time of LTX, 65% of the patients were older than 55 years. An age > 55 years also correlated with the incidence of TE (p = 0.037) and these patients had reduced overall post-transplant survival when the event occurred within the first postoperative year (59% vs. 72%, p = 0.028). CONCLUSIONS: The incidence of TE after LTX is high, especially in lung transplant recipients with a BMI > 25 and an age > 55 years as well as cardiovascular risk factors closely associated with the metabolic syndrome. As these patients comprise a growing recipient fraction, intensified research should focus on the risks and benefits of regular screening or a prolonged TE prophylaxis in these patients. Trial registration number DKRS: 00021501.

Targeting cluster of differentiation 26 / dipeptidyl peptidase 4 (CD26/DPP4) in organ fibrosis.

Cluster of differentiation 26 (CD26)/dipeptidyl peptidase 4 (DPP4) is an exopeptidase that is expressed as a transmembrane protein in many organs but also present in a circulating soluble form. Beyond its enzymatic and costimulatory activity, CD26/DPP4 is involved in the pathogenesis of chronic fibrotic diseases across many organ types, such as liver cirrhosis, kidney fibrosis and lung fibrosis. Organ fibrosis is associated with a high morbidity and mortality, and there are no causative therapies that can effectively attenuate the progress of the disease. Growing evidence suggests that inhibiting CD26/DPP4 can modulate the profibrotic tissue microenvironment and thus reduce fibrotic changes within affected organs. This review summarizes the role of CD26/DPP4 in fibroproliferative disorders and highlights new opportunities for an antifibrotic treatment by CD26/DPP4 inhibition. As a major advantage, CD26/DPP4 inhibitors have been in safe and routine clinical use in type 2 diabetes for many years and thus qualify for repurposing to repurpose as a promising therapeutic against fibrosis. LINKED ARTICLES: This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc.

The Impact of Postoperative Pulmonary Complications on Perioperative Outcomes in Patients Undergoing Pneumonectomy: A Multicenter Retrospective Cohort Study of the German Thorax Registry.

Postoperative pulmonary complications have a deleterious impact in regards to thoracic surgery. Pneumonectomy is associated with the highest perioperative risk in elective thoracic surgery. The data from 152 patients undergoing pneumonectomy in this multicenter retrospective study were extracted from the German Thorax Registry database and presented after univariate and multivariate statistical processing. This retrospective study investigated the incidence of postoperative pulmonary complications (PPCs) and their impact on perioperative morbidity and mortality. Patient-specific, preoperative, procedural, and postoperative risk factors for PPCs and in-hospital mortality were analyzed. A total of 32 (21%) patients exhibited one or more PPCs, and 11 (7%) died during the hospital stay. Multivariate stepwise logistic regression identified a preoperative FEV1 < 50% (OR 9.1, 95% CI 1.9-67), the presence of medical complications (OR 7.4, 95% CI 2.7-16.2), and an ICU stay of more than 2 days (OR 14, 95% CI 3.9-59) as independent factors associated with PPCs. PPCs (OR 13, 95% CI 3.2-52), a preoperative FEV1 < 60% in patients with previous pulmonary infection (OR 21, 95% CI 3.2-52), and continued postoperative mechanical ventilation (OR 8.4, 95% CI 2-34) were independent factors for in-hospital mortality. Our data emphasizes that PPCs are a significant risk factor for morbidity and mortality after pneumonectomy. Intensified perioperative care targeting the underlying risk factors and effects of PPCs, postoperative ventilation, and preoperative respiratory infections, especially in patients with reduced pulmonary reserve, could improve patient outcomes.

Lung Abscess and Recurrent Empyema After Infection With Mycoplasma hominis: A Case Report and Review of the Literature.

Mycoplasma hominis is a rarely identified cause of respiratory infection that can cause significant morbidity and mortality in immunocompromised patients. It is often missed due to the difficult detection of the organism with routine laboratory methods. We present the case of a 63-year-old male with a history of lymphoma who was transferred to our hospital with recurrent right-sided empyema and lung abscess in the right lower lobe. Advanced microbiological analysis finally revealed infection with M hominis. Despite appropriate antibiotic treatment, prolonged drainage as well as repeated surgery, which eventually resulted in right lower bilobectomy, were necessary for clinical improvement of our patient. Infection with M hominis may be more prevalent than previously indicated and can cause severe morbidity and mortality in thoracic surgery patients. Due to the diagnostic challenge, the appropriate antimicrobial treatment is often delayed. Inherent resistance to macrolides and inactivity of cell wall-active agents potentially complicate empiric antibiotic therapy. A review of the currently available literature enables a better understanding of the diagnostic difficulties and importance of this infection.

Pulmonary laser-assisted metastasectomy is associated with prolonged survival in patients with colorectal cancer.

BACKGROUND: Pulmonary metastases develop in 10-15% of patients with colorectal cancer. Surgical metastasectomy currently provides the only hope for a cure for these patients. The aim of this study was to analyze the expanding role of pulmonary metastasectomy in the context of laser-assisted surgery (LAS) vs. non-laser-assisted surgery (NLAS). METHODS: We performed a single-center retrospective analysis of 204 patients who underwent curative pulmonary metastasectomy for colorectal cancer between 01/2005 and 12/2016. The main endpoint was survival. The Kaplan-Meier method was applied for statistical analysis and survival rates were compared with the log rank test. RESULTS: Median follow-up was 53 months. A total of 267 metastases were resected in 154 operations in the NLAS group (median: 1) vs. 438 metastases in 122 operations in the LAS group (median: 5; P<0.0001). The interval between treatment of the primary tumor and the first pulmonary metastasectomy was significantly shorter in the LAS group (19 vs. 32 months; P=0.008). Anatomical resections were significantly reduced using LAS, 8% vs. 23% respectively. Despite more negative predictors in the LAS group, there was no statistically significant difference in overall disease-specific 5-year survival (70% LAS vs. 58% NLAS; P=0.18). CONCLUSIONS: Survival after pulmonary metastasectomy has previously been shown to correlate with a low number of metastases and a longer disease-free interval. However, with the tissue-saving LAS technique complete resectability can be achieved in patients with more metastases and long-term survival is possible for selected patients.

The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases.

Fe(II)- and 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are "epigenetic eraser" enzymes involved in the regulation of gene expression and are emerging drug targets in oncology. We screened a set of clinically used iron chelators and report that they potently inhibit JMJD2A (KDM4A) in vitro. Mode of action investigations revealed that one compound, deferasirox, is a bona fide active site-binding inhibitor as shown by kinetic and spectroscopic studies. Synthesis of derivatives with improved cell permeability resulted in significant upregulation of histone trimethylation and potent cancer cell growth inhibition. Deferasirox was also found to inhibit human 2OG-dependent hypoxia inducible factor prolyl hydroxylase activity. Therapeutic effects of clinically used deferasirox may thus involve transcriptional regulation through 2OG oxygenase inhibition. Deferasirox might provide a useful starting point for the development of novel anticancer drugs targeting 2OG oxygenases and a valuable tool compound for investigations of KDM function.

Mucinous cystadenocarcinoma arising from mucinous cystadenoma of the lung: case report and review of the literature.

Mucinous cystadenoma is a benign tumor commonly found in the pancreas, the ovaries or the appendix. Only very few cases of these tumors originating from the lungs have been reported worldwide, with even less cases describing malignant transformation. We present the case of a 58-year-old woman with a history of recurrent pulmonary infections who underwent left upper lobectomy for lung abscess and was initially diagnosed with pulmonary mucinous cystadenoma (PMCA). Upon thorough immunohistochemical workup, especially due to carcinoembryonic antigen (CEA) positivity, intramucinous singlet cells were eventually diagnostic for invasive carcinoma, in this case a mucinous cystadenocarcinoma arising from a PCMA. PMCA is a rare benign tumor whose potential for malignant transformation has not yet been fully understood. Due to the low number of cases further studies are needed to evaluate if there is a benefit of complete oncologic resection, provided the general condition of the patient allows it. A review of the currently available literature serves to better understand the clinical, radiological and histological features of this rare tumor.

Pulmonary metastasectomy for thyroid cancer as salvage therapy for radioactive iodine-refractory metastases.

OBJECTIVES: Distant metastasis arising from thyroid cancer is rare but has been associated with significantly reduced long-term survival, especially when refractory to radioactive iodine ablation. We provide one of the largest studies worldwide reporting the outcome after salvage pulmonary metastasectomy for this entity, aiming to identify prognostic factors and to analyse surgical indication. METHODS: We retrospectively analysed the medical records of 43 patients who had undergone pulmonary metastasectomy for radioactive iodine-refractory thyroid cancer from 1985 to 2016. RESULTS: The median follow-up period was 77 (95% confidence interval 41-113) months. Twenty-three (53%) patients were alive at the time of analysis. The majority of tumours were follicular thyroid cancer by histology, with 23% identified as Hurthle cell subtype. Five- and 10-year disease-specific (DS) survival was 84% and 59%, respectively. Thirty-one (72%) patients underwent R0-resection with a 5- and 10-year DS survival of 100% and 77%, respectively. This was significantly reduced to 62% and 22% (P = 0.013) in case of incomplete resection, respectively. Ten years after R0-metastasectomy, 17 (55%) patients were recurrence-free. Systematic mediastinal lymphadenectomy was performed in 16 (37%) patients and was associated with improved long-term DS survival (10 years 88% vs 46%, P = 0.034). Moreover, a reduction of > 80% in serum thyroglobulin levels post-metastasectomy correlates with better long-term DS survival (10 years 81% vs 36%, P = 0.007). CONCLUSIONS: Pulmonary metastasectomy is associated with good survival for selected patients with radioactive iodine-refractory metastases of differentiated thyroid cancer, especially if R0-resection can be achieved. Moreover, it is worth considering whether a significant reduction of tumour load, as indicated by thyroglobulin serum levels, seems possible.

miRNAs as modulators of angiogenesis.

MicroRNAs are highly expressed in endothelial cells, and recent data suggest that they regulate aspects of vascular development and angiogenesis. This study highlights the state of the art in this field and potential therapeutic opportunities. MicroRNAs (miRNAs) represent a family of conserved short (≈22 nt) noncoding single-stranded RNAs that have been identified in plants and animals. They are generated by the sequential processing of the RNA template by the enzymes Drosha and Dicer, and mature miRNAs can regulate the levels of gene expression at the posttranscriptional level. miRNAs participate in a diverse range of regulatory events via regulation of genes involved in the control of processes such as development, differentiation, homeostasis, metabolism, growth, proliferation, and apoptosis. However, rather than functioning as regulatory on-off switches, miRNAs often function to modulate or fine-tune cellular phenotypes. So far, more than 1000 mammalian miRNAs have been identified since the discovery of the first two miRNAs (lin-4 and let-7), and bioinformatics predictions indicate that mammalian miRNAs can regulate ∼30% of all protein-coding genes.

11,12-EET stimulates the association of BK channel α and ß(1) subunits in mitochondria to induce pulmonary vasoconstriction.

In the systemic circulation, 11,12-epoxyeicosatrienoic acid (11,12-EET) elicits nitric oxide (NO)- and prostacyclin-independent vascular relaxation, partially through the activation of large conductance Ca(2+)-activated potassium (BK) channels. However, in the lung 11,12-EET contributes to hypoxia-induced pulmonary vasoconstriction. Since pulmonary artery smooth muscle cells also express BK channels, we assessed the consequences of BKß(1) subunit deletion on pulmonary responsiveness to 11,12-EET as well as to acute hypoxia. In buffer-perfused mouse lungs, hypoxia increased pulmonary artery pressure and this was significantly enhanced in the presence of NO synthase (NOS) and cyclooxygenase (COX) inhibitors. Under these conditions the elevation of tissue EET levels using an inhibitor of the soluble epoxide hydrolase (sEH-I), further increased the hypoxic contraction. Direct administration of 11,12-EET also increased pulmonary artery pressure, and both the sEH-I and 11,12-EET effects were prevented by iberiotoxin and absent in BKß(1)(-/-) mice. In pulmonary artery smooth muscle cells treated with NOS and COX inhibitors and loaded with the potentiometric dye, di-8-ANEPPS, 11,12-EET induced depolarization while the BK channel opener NS1619 elicited hyperpolarization indicating there was no effect of the EET on classical plasma membrane BK channels. In pulmonary artery smooth muscle cells a subpopulation of BK channels is localized in mitochondria. In these cells, 11,12-EET elicited an iberiotoxin-sensitive loss of mitochondrial membrane potential (JC-1 fluorescence) leading to plasma membrane depolarization, an effect not observed in BKß(1)(-/-) cells. Mechanistically, stimulation with 11,12-EET time-dependently induced the association of the BK α and ß(1) subunits. Our data indicate that in the absence of NO and prostacyclin 11,12-EET contributes to pulmonary vasoconstriction by stimulating the association of the α and ß(1) subunits of mitochondrial BK channels. The 11,12-EET-induced activation of BK channels results in loss of the mitochondrial membrane potential and depolarization of the pulmonary artery smooth muscle cells.