Outcomes of oncological intended thoracic surgery after lung transplantation.

Background: Lung cancer following lung transplantation (LT) may require thoracic surgery (TS). There is an urgent need for data on surgical feasibility, clinical and surgical characteristics, as well as outcome data. Methods: We reviewed the medical records of LT patients who had undergone TS at the University Hospital Leipzig between the years 2000 and 2022. Data on medical and surgical history, pulmonary function test, arterial blood gas analysis, six-minute walking distance test, and surgical approach, perioperative management, anesthesiologic, and surgical procedures were analyzed. Results: Among 248 LT patients, 13 patients (5.2%) developed lung cancer after 4.2 years on average and on 6 of them (46.2%), major TS procedure was performed for the resection of lung cancer. In one patient who underwent TS for a suspicious pulmonary nodule, it turned out to be a parenchymal scar. TS was carried out in 57.1% on the native lung and 42.9% on the transplant lung. Pneumonia and acute renal failure were predominantly observed postoperative complications. We found that the capacity of gas exchange either before or after TS was related to the degree of postoperative complications. The in-hospital survival was 71.4%. Conclusions: Incidence of lung cancer is increased after LT. Follow-up care allows early diagnosis with a comparably high share of operable tumor stage. Cancer as well as postoperative complications were more likely after single lung transplantation (SLT). Postoperative morbidity and mortality are higher in this scarce group of patients and hence, warrants a centered and experienced interdisciplinary approach.

New developments in the imaging of lung cancer.

Radiological and nuclear medicine methods play a fundamental role in the diagnosis and staging of patients with lung cancer. Imaging is essential in the detection, characterisation, staging and follow-up of lung cancer. Due to the increasing evidence, low-dose chest computed tomography (CT) screening for the early detection of lung cancer is being introduced to the clinical routine in several countries. Radiomics and radiogenomics are emerging fields reliant on artificial intelligence to improve diagnosis and personalised risk stratification. Ultrasound- and CT-guided interventions are minimally invasive methods for the diagnosis and treatment of pulmonary malignancies. In this review, we put more emphasis on the new developments in the imaging of lung cancer.

Comparative bioinformatic analysis of KRAS, STK11 and KEAP1 (co-)mutations in non-small cell lung cancer with a special focus on KRAS G12C.

OBJECTIVES: Mutations in STK11 (STK11MUT) and KEAP1 (KEAP1MUT) occur frequently in non-small cell lung cancer (NSCLC) and are often co-mutated with KRAS. Several studies linked the co-occurrence of KRASMUT + STK11MUT, as well as KRASMUT + KEAP1MUT to reduced response to immune checkpoint inhibitors (ICI) and even a negative impact on survival. Data focusing STK11 + KEAP1 co-mutations or the triple mutation (KRAS + STK11 + KEAP1) are scarce. The recent availability of KRAS-G12C inhibitors increases the clinical relevance of those co-mutations in KRAS-mutated NSCLC. MATERIALS AND METHODS: We present a comprehensive bioinformatic analysis encompassing six datasets retrieved from cBioPortal. RESULTS: Independent of the treatment, triple mutations and STK11MUT + KEAP1MUT were significantly associated with a reduced overall survival (OS). Across treatments, OS of patients with a KRAS G12C triple mutation was significantly reduced compared to patients with KRAS G12C-only. Under ICI-therapy, there was no significant difference in OS between patients harboring the KRAS G12C-only and patients with the KRAS G12C triple mutation, but a significant difference between patients harboring KRAS non-G12C and KRAS non-G12C triple mutations. Triple mutated primary tumors showed a significantly increased frequency of distant metastases to bone and adrenal glands compared to KRAS-only mutated tumors. Additionally, our drug response analysis in cancer cell lines harboring the triple mutations revealed the WNT pathway inhibitor XAV-939 as a potential future drug candidate for this mutational situation. CONCLUSION: The triple mutation status may serve as a negative prognostic and predictive factor across treatments compared to KRASMUT-only. KRAS G12C generally seems to be a negative predictive marker for ICI-therapy.

Renal function is a major predictor of circulating acyl-CoA-binding protein/diazepam-binding inhibitor.

Objective: Acyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has lately been described as an endocrine factor affecting food intake and lipid metabolism. ACBP is dysregulated in catabolic/malnutrition states like sepsis or systemic inflammation. However, regulation of ACBP has not been investigated in conditions with impaired kidney function, so far. Design/methods: Serum ACBP concentrations were investigated by enzyme-linked immunosorbent assay i) in a cohort of 60 individuals with kidney failure (KF) on chronic haemodialysis and compared to 60 individuals with a preserved kidney function; and ii) in a human model of acute kidney dysfunction (AKD). In addition, mACBP mRNA expression was assessed in two CKD mouse models and in two distinct groups of non-CKD mice. Further, mRNA expression of mACBP was measured in vitro in isolated, differentiated mouse adipocytes - brown and white - after exposure to the uremic agent indoxyl sulfate. Results: Median [interquartile range] serum ACBP was almost 20-fold increased in KF (514.0 [339.3] µg/l) compared to subjects without KF (26.1 [39.1] µg/l) (p<0.001). eGFR was the most important, inverse predictor of circulating ACBP in multivariate analysis (standardized ß=-0.839; p<0.001). Furthermore, AKD increased ACBP concentrations almost 3-fold (p<0.001). Increased ACBP levels were not caused by augmented mACBP mRNA expression in different tissues of CKD mice in vivo or in indoxyl sulfate-treated adipocytes in vitro. Conclusions: Circulating ACBP inversely associates with renal function, most likely through renal retention of the cytokine. Future studies need to investigate ACBP physiology in malnutrition-related disease states, such as CKD, and to adjust for markers of renal function.

In-Depth Analysis of the Re-Emergence of Respiratory Syncytial Virus at a Tertiary Care Hospital in Germany in the Summer of 2021 after the Alleviation of Non-Pharmaceutical Interventions Due to the SARS-CoV-2 Pandemic.

Following the extensive non-pharmaceutical interventions (NPIs) and behavioral changes in the wake of the SARS-CoV-2 pandemic, an interseasonal rise in respiratory syncytial virus (RSV) cases was observed in Germany in 2021. The aim of this study was to characterize the local molecular epidemiology of RSV infections in comparison to the three pre-pandemic seasons. Additionally, clinical data were retrieved from patient charts to determine the clinical significance of RSV infections. RSV detections peaked in calendar week 40 of 2021, 18 weeks earlier than the usual peak observed in the three pre-pandemic seasons. Sequence analysis revealed a close phylogenetic relatedness regardless of the season of origin. A significantly higher amount of pediatric cases (88.9% of all cases, p < 0.001) was observed for season 2021/2022. For the pediatric cases, significant differences were observed for an increased number of siblings in the household (p = 0.004), a lower rate of fever (p = 0.007), and a reduced amount of co-infections (p = 0.001). Although the mean age of the adult patients was significantly younger (47.1 vs. 64.7, p < 0.001), high rates of comorbidities, lower respiratory tract infections and intensive care unit admissions prevailed. The NPIs in the wake of the SARS-CoV-2 pandemic had a tremendous impact on the epidemiologic characteristics and seasonality of RSV and warrant further epidemiologic studies of this important pathogen.

IGFBP3 inhibits tumor growth and invasion of lung cancer cells and is associated with improved survival in lung cancer patients.

The insulin-like growth factor (IGF)-pathway is involved in tumor cell proliferation, metastasis, and survival. We aimed to find out what effects IGF binding protein 3 (IGFBP3) exerted on H1299 lung cancer (LC) cells in terms of tumor growth and invasion and whether IGFBP3 was associated with clinical and pathological parameters in a prospective cohort of LC patients. H1299 cells were transfected with an IGFBP3-expressing vector. Its influence on apoptosis induction via flow cytometry annexin V FITC assay, cell proliferation in 2D and 3D cell culture, and invasion were examined. Expression of several matrix metalloproteinases (MMPs) and inhibitors (TIMP-1) were also investigated in IGFBP3-transfected LC cells. Further, data on LC patients (n = 131), tumor characteristics, and survival were prospectively collected and correlated with IGFBP3 plasma levels. IGFBP3 did not influence apoptosis induction and 2D cell proliferation. However, both spheroid growth (3D proliferation) and invasion of IGFBP3-transfected cells planted in an extracellular matrix-based gel were significantly inhibited. IGFBP3 inhibited MMP-1 release, and the total MMP activity. In LC patients, higher IGFBP3 plasma levels correlated with both lower clinical tumor stage, grading, Ki-67 staining, and the absence of necrosis (P < 0.05, respectively). Increased IGFBP3 plasma levels were associated with improved overall survival (hazard ratio 0.37, P = 0.01). In conclusion, overexpressed IGFBP3 in a LC cell line inhibited tumor growth and invasion. Translating from bench to bedside, investigation of clinicopathological parameters confirmed these experimental results showing that higher IGFBP3 plasma levels were associated with less aggressive tumor growth, reduced tumor spread, and improved survival of LC patients.

CT texture analysis and node-RADS CT score of mediastinal lymph nodes - diagnostic performance in lung cancer patients.

BACKGROUND: Texture analysis derived from computed tomography (CT) can provide clinically relevant imaging biomarkers. Node-RADS is a recently proposed classification to categorize lymph nodes in radiological images. The present study sought to investigate the diagnostic abilities of CT texture analysis and Node-RADS to discriminate benign from malignant mediastinal lymph nodes in patients with lung cancer. METHODS: Ninety-one patients (n = 32 females, 35%) with a mean age of 64.8 ± 10.8 years were included in this retrospective study. Texture analysis was performed using the free available Mazda software. All lymph nodes were scored accordingly to the Node-RADS classification. All primary tumors and all investigated mediastinal lymph nodes were histopathologically confirmed during clinical workup. RESULTS: In discrimination analysis, Node-RADS score showed statistically significant differences between N0 and N1-3 (p < 0.001). Multiple texture features were different between benign and malignant lymph nodes: S(1,0)AngScMom, S(1,0)SumEntrp, S(1,0)Entropy, S(0,1)SumAverg. Correlation analysis revealed positive associations between the texture features with Node-RADS score: S(4,0)Entropy (r = 0.72, p < 0.001), S(3,0) Entropy (r = 0.72, p < 0.001), S(2,2)Entropy (r = 0.72, p < 0.001). CONCLUSIONS: Several texture features and Node-RADS derived from CT were associated with the malignancy of mediastinal lymph nodes and might therefore be helpful for discrimination purposes. Both of the two quantitative assessments could be translated and used in clinical routine.

CT Texture Analysis of Pulmonary Neuroendocrine Tumors-Associations with Tumor Grading and Proliferation.

Texture analysis derived from computed tomography (CT) might be able to provide clinically relevant imaging biomarkers and might be associated with histopathological features in tumors. The present study sought to elucidate the possible associations between texture features derived from CT images with proliferation index Ki-67 and grading in pulmonary neuroendocrine tumors. Overall, 38 patients (n = 22 females, 58%) with a mean age of 60.8 ± 15.2 years were included into this retrospective study. The texture analysis was performed using the free available Mazda software. All tumors were histopathologically confirmed. In discrimination analysis, "S(1,1)SumEntrp" was significantly different between typical and atypical carcinoids (mean 1.74 ± 0.11 versus 1.79 ± 0.14, p = 0.007). The correlation analysis revealed a moderate positive association between Ki-67 index with the first order parameter kurtosis (r = 0.66, p = 0.001). Several other texture features were associated with the Ki-67 index, the highest correlation coefficient showed "S(4,4)InvDfMom" (r = 0.59, p = 0.004). Several texture features derived from CT were associated with the proliferation index Ki-67 and might therefore be a valuable novel biomarker in pulmonary neuroendocrine tumors. "Sumentrp" might be a promising parameter to aid in the discrimination between typical and atypical carcinoids.

[Thoracolumbar back pain as the leading symptom of a marked COVID-19 pneumonia]. / Thorakolumbaler Rückenschmerz als führendes Symptom einer ausgeprägten COVID-19-Pneumonie.

HISTORY: A 49-year-old male patient visited the surgical outpatient clinic with new onset low back pain. The pain was increasing for nine days and he did not have any signs of a respiratory infection, in particular neither fever nor cough. INVESTIGATIONS: During the further examination and unclothing, mild dyspnea was apparent. According to the patient, the dyspnea was also progressive in the last days but would not affect everyday life. Furthermore, the patient reported a significant and unintended weight loss. Outpatient chest X-ray revealed bilateral, peripheral, fine-speckled infiltrates that became increasingly confluent. Polymerase chain reaction analysis of the nasopharyngeal swab was positive for SARS-CoV-2 (wild type). TREATMENT AND COURSE: Due to progressive dyspnea, the patient was referred to inpatient treatment within the day, where he rapidly developed severe acute respiratory failure. To provide respiratory support, a combined intermittent non-invasive ventilation and nasal high flow-therapy was started. Moreover, a probatory antiviral therapy with remdesivir was initiated. Since a bacterial superinfection was suspected, additional antibiotic therapy was ordered. After 13 days of inpatient treatment, the patient was discharged. The low back pain receded completely during inpatient treatment without any specific therapy. CONCLUSIONS: Low back pain can be a symptom of COVID-19. In our case report, it was the only complain that led to the outpatient consultation. Even though back pain is a very common symptom in everyday practice, one should keep unusual causes in mind.

Associations of aspirin, statins and metformin with lung cancer risk and related mortality.

Given the poor survival of lung cancer patients and the promising observations herein, future studies (RCTs) should further investigate both time- and dose-dependent effects of combination therapies across all categories of prevention of lung cancer. https://bit.ly/3hlYTtY.

Increased pulmonary serotonin transporter in patients with chronic obstructive pulmonary disease who developed pulmonary hypertension.

PURPOSE: Pulmonary hypertension (PH) is characterized by a progressive remodelling of the pulmonary vasculature resulting in right heart failure and eventually death. The serotonin transporter (SERT) may be involved in the pathogenesis of PH in patients with chronic-obstructive pulmonary disease (COPD). This study investigated for the first time the SERT in vivo availability in the lungs of patients with COPD and PH (COPD+PH). METHODS: SERT availability was assessed using SERT-selective [11C]DASB and positron emission tomography/computed tomography (PET/CT) with dynamic acquisition over 30 min in 4 groups of 5 participants each: COPD, COPD+PH, pulmonary arterial hypertension, and a healthy control (HC). Time activity curves were generated based on a volume of interest within the middle lobe. Tissue-to-blood concentration ratios after 25 to 30 min (TTBR25-30) served as receptor parameter for group comparison and were corrected for lung tissue attenuation. Participants underwent comprehensive pulmonary workup. Statistical analysis included group comparisons and correlation analysis. RESULTS: [11C]DASB uptake peak values did not differ among the cohorts after adjusting for lung tissue attenuation, suggesting equal radiotracer delivery. Both the COPD and COPD+PH cohort showed significantly lower TTBR25-30 values after correction for lung attenuation than HC. Attenuation corrected TTBR25-30 values were significantly higher in the COPD+PH cohort than those in the COPD cohort and higher in non-smokers than in smokers. They positively correlated with invasively measured severity of PH and inversely with airflow limitation and emphysema. Considering all COPD patients ± PH, they positively correlated with right heart strain (NT-proBNP). CONCLUSION: By applying [11C]DASB and PET/CT, semiquantitative measures of SERT availability are demonstrated in the lung vasculature of patients with COPD and/or PH. COPD patients who developed PH show increased pulmonary [11C]DASB uptake compared to COPD patients without PH indicating an implication of pulmonary SERT in the development of PH in COPD patients.

Lung cancer incidence and mortality with extended follow-up in the National LungScreening Trial.

The extended follow-up of the NLST represents a timely and important update to the NLST data, alongside full results of the NELSON and the LUSI trials, as Europe begins to set out a vision for lung cancer screening. http://bit.ly/2MYXedI.

Multidisciplinary care models for patients with lung cancer.

Multidisciplinary care is the cornerstone of lung cancer treatment in the developed world, even though there is a relative lack of consistent evidence that this care model improves outcomes. In this review, we present the available literature regarding how to set up and run an efficient multidisciplinary care model for lung cancer patients with emphasis on team members' roles and responsibilities. Moreover, we present some limited evidence about multidisciplinary care and its impact on lung cancer outcomes and survival. This review provides simple guidance on setting up and running a multidisciplinary service for lung cancer patients. It highlights the importance of defined roles and responsibilities for team members. It also presents concise information based on the literature regarding the impact of multidisciplinary care in lung cancer outcomes (e.g. survival of patients undergoing lung cancer surgery).

Oxygen devices and delivery systems.

Oxygen use has extended from inpatient to outpatient settings for patients with chronic pulmonary diseases and complications of hypoxaemia. This article presents an overview of oxygen devices (oxygen concentrators, compressed gas cylinders and liquid oxygen) and delivery systems (high- and low-flow). The indications, advantages and disadvantages of each device and delivery system are presented, aiming to offer updated knowledge to the multidisciplinary team members managing patients with respiratory failure, and therefore allowing appropriate selection of devices and delivery systems that are tailored to the needs of each patient.

High amplitude stretching of ATII cells and fibroblasts results in profibrotic effects.

Background: Inappropriate mechanical forces act on alveolar epithelial cells during mechanical ventilation e.g. in ARDS and possibly in patients with pulmonary fibrosis. These forces can cause lung injury and may contribute to the development or aggravation of pulmonary fibrosis. Aim of the study: We investigated the hypothesis that high amplitude mechanical stretching of alveolar type II (ATII) cells and lung fibroblasts promotes profibrotic processes. Material and Methods: ATII cells and fibroblasts were stretched on elastic membranes using a pattern of higher amplitudes ("unphysiological"). The production of profibrotic cytokines and extra cellular matrix (ECM) proteins were investigated in supernatants. In addition, we determined the expression of relevant microRNAs (miRNA) and the process of epithelial-mesenchymal transition (EMT) in ATII cells. Results: Unphysiological stretch of ATII cells led to increased release of TGF-ß1 into supernatants. We also found elevated protein levels of collagen I and IV in supernatants of stretched cells. By contrast, stretching of fibroblasts changed neither the expression of fibrosis-modulating factors nor ECM-proteins. However, fibroblasts significantly withstood stretch-induced cell injury and seemed to have a survival benefit. Further, stretched ATII cells exhibited a higher expression of miRNAs (miR-15b, miR-25, let-7d) relevant to EMT. The process of EMT, which is characterized by an increase of vimentin and a decrease of cytokeratin expression, was significantly accelerated due to stretching of ATII cells. Conclusion: These data provide evidence that unphysiological mechanical stretching of lung cells induced several profibrotic effects and accelerated EMT, which may have critical implications in terms of development or aggravation of pulmonary fibrosis in the clinical context.

The brown fat-secreted adipokine neuregulin 4 is decreased in human and murine chronic kidney disease.

OBJECTIVE: Neuregulin 4 (NRG4) has recently been introduced as a novel brown adipose tissue (BAT)-secreted adipokine with beneficial metabolic effects in mice. However, regulation of Nrg4 in end-stage kidney disease (ESKD) and type 2 diabetes mellitus (T2DM) has not been elucidated, so far. DESIGN/METHODS: Serum NRG4 levels were quantified by ELISA in 60 subjects with ESKD on chronic hemodialysis as compared to 60 subjects with an estimated glomerular filtration rate >50 mL/min/1.73 m2 in a cross-sectional cohort. Within both groups, about half of the patients had a T2DM. Furthermore, mRNA expression of Nrg4 was determined in two mouse models of diabetic kidney disease (DKD) as compared to two different groups of non-diabetic control mice. Moreover, mRNA expression of Nrg4 was investigated in cultured, differentiated mouse brown and white adipocytes, as well as hepatocytes, after treatment with the uremic toxin indoxyl sulfate. RESULTS: Median serum NRG4 was significantly lower in patients with ESKD compared to controls and the adipokine was independently associated with a beneficial renal, glucose and lipid profile. In mice with DKD, Nrg4 mRNA expression was decreased in all adipose tissue depots compared to control mice. The uremic toxin indoxyl sulfate did not significantly alter Nrg4 mRNA expression in adipocytes and hepatocytes, in vitro. CONCLUSIONS: Circulating NRG4 is independently associated with a preserved renal function and mRNA expression of -Nrg4 is reduced in adipose tissue depots of mice with DKD. The BAT-secreted adipokine is further associated with a beneficial glucose and lipid profile supporting NRG4 as potential treatment target in metabolic and renal disease states.

No erythropoietin-induced growth is observed in non-small cell lung cancer cells.

Lung cancer patients have the highest incidence of anemia among patients with solid tumors. The use of recombinant human erythropoietin (Epo) has consistently been shown to reduce the need for blood transfusions and to increase hemoglobin levels in lung cancer patients with chemotherapy-induced anemia. However, clinical and preclinical studies have prompted concerns that Epo and the presence of its receptor, EpoR, in tumor cells may be responsible for adverse effects and, eventually, death. The question has been raised whether Epo promotes tumor growth and inhibits the death of cancer cells. In this study, we investigated the presence and functionality of EpoR, as well as the implications of Epo upon the proliferation and survival of lung cancer cells. Since the protein expression of both Epo and EpoR is induced by hypoxia, which is frequently present in lung cancer, the cells were treated with Epo under both normoxic and hypoxic conditions (1% O2). By using quantitative (real-time) PCR, western blot analysis, and immunocytochemical staining, three non-small cell lung cancer (NSCLC) cell lines (A427, A549 and NCI-H358) were analyzed for the expression of EpoR and its specific downstream signaling pathways [Janus kinase 2 (Jak2)-signal transducer and activator of transcription 5 (STAT5), phosphatidylinositol-3-kinase (PI3K)-Akt, mitogen-activated protein (MAP) kinase]. The effects of 100 U/ml Epo on cell proliferation and cisplatin-induced apoptosis were assessed. All NSCLC cell lines expressed EpoR mRNA and protein, while these levels differed considerably between the cell lines. We found the constitutive phosphorylation of EpoR and most of its downstream signaling pathways (STAT5, Akt and ERK1/2) independently of Epo administration. While Epo markedly enhanced the proliferation and reduced apoptosis of Epo-dependent UT-7/Epo leukemia cells, it did not affect tumor cell proliferation or the cisplatin-induced apoptosis of NSCLC cells. Thus, this in vitro study suggests that there are no tumor-promoting effects of Epo in the NSCLC cell lines studied, neither under normoxic nor under hypoxic conditions.