Transcriptional activators YAP/TAZ and AXL orchestrate dedifferentiation, cell fate, and metastasis in human osteosarcoma.

Osteosarcoma (OS) is a molecularly heterogeneous, aggressive, poorly differentiated pediatric bone cancer that frequently spreads to the lung. Relatively little is known about phenotypic and epigenetic changes that promote lung metastases. To identify key drivers of metastasis, we studied human CCH-OS-D OS cells within a previously described rat acellular lung (ACL) model that preserves the native lung architecture, extracellular matrix, and capillary network. This system identified a subset of cells-termed derived circulating tumor cells (dCTCs)-that can migrate, intravasate, and spread within a bioreactor-perfused capillary network. Remarkably, dCTCs highly expressed epithelial-to-mesenchymal transition (EMT)-associated transcription factors (EMT-TFs), such as ZEB1, TWIST, and SOX9, which suggests that they undergo cellular reprogramming toward a less differentiated state by coopting the same epigenetic machinery used by carcinomas. Since YAP/TAZ and AXL tightly regulate the fate and plasticity of normal mesenchymal cells in response to microenvironmental cues, we explored whether these proteins contributed to OS metastatic potential using an isogenic pair of human OS cell lines that differ in AXL expression. We show that AXL inhibition significantly reduced the number of MG63.2 pulmonary metastases in murine models. Collectively, we present a laboratory-based method to detect and characterize a pure population of dCTCs, which provides a unique opportunity to study how OS cell fate and differentiation contributes to metastatic potential. Though the important step of clinical validation remains, our identification of AXL, ZEB1, and TWIST upregulation raises the tantalizing prospect that EMT-TF-directed therapies might expand the arsenal of therapies used to combat advanced-stage OS.

The association between surgical duration and venous thromboembolism in outpatient surgery: A propensity score adjusted prospective cohort study.

BACKGROUND: Outpatient surgeries account for 60-70% of all procedures. Increased surgical duration has been demonstrated to be an independent risk factor for the development of venous thromboembolism (VTEs) after inpatient surgeries. In contrast, it is currently unknown if surgical duration increases the risk of VTEs for outpatient surgeries. MATERIALS AND METHODS: The 2005 through 2016 NSQIP Participant Use Data Files were queried to extract all patients scheduled for outpatient surgery. A z-score for surgical duration was calculated for each procedure to allow for standardization across surgeries of expected shorter or longer duration. The primary outcome measured was incidence of VTEs within 30 days of surgery. RESULTS: A total of 3474 patients out of 1,863,523 (0.19%) had a VTE. After adjusting for confounding factors, the first and fifth quintiles compared to the middle quintile had odds ratios (ORs) of 0.75 (95% CI 0.68, 0.80) and 1.43 (95% CI, 1.35%-1.52%), respectively, P < 0.001. Patients who developed VTEs were more likely to be readmitted to the hospital, OR (95%CI) of 51.9 (48.0-56.2), C statistic = 0.67. CONCLUSION: Surgical duration is associated with the development of VTEs after outpatient surgery. While the overall incidence of VTE is low and does not require generalized prophylaxis, clinical practitioners should consider prophylaxis for patients undergoing outpatient surgery performed with excessive time compared to the average surgical procedure duration.

The Effect of Intraoperative Methadone Compared to Morphine on Postsurgical Pain: A Meta-Analysis of Randomized Controlled Trials.

METHODS: We performed a quantitative systematic review of randomized controlled trials in PubMed, Embase, Cochrane Library, and Google Scholar electronic databases. Meta-analysis was performed using the random effects model, weighted mean differences (WMD), standard deviation, 95% confidence intervals, and sample size. Methodological quality was evaluated using Cochrane Collaboration's tool. RESULTS: Seven randomized controlled trials evaluating 337 patients across different surgical procedures were included. The aggregated effect of intraoperative methadone on postoperative opioid consumption did not reveal a significant effect, WMD (95% CI) of -0.51 (-1.79 to 0.76), (P=0.43) IV morphine equivalents. In contrast, the effect of methadone on postoperative pain demonstrated a significant effect in the postanesthesia care unit, WMD (95% CI) of -1.11 (-1.88 to -0.33), P=0.005, and at 24 hours, WMD (95% CI) of -1.35 (-2.03 to -0.67), P < 0.001. CONCLUSIONS: The use of intraoperative methadone reduces postoperative pain when compared to morphine. In addition, the beneficial effect of methadone on postoperative pain is not attributable to an increase in postsurgical opioid consumption. Our results suggest that intraoperative methadone may be a viable strategy to reduce acute pain in surgical patients.

Small cell and non small cell lung cancer form metastasis on cellular 4D lung model.

BACKGROUND: Metastasis is the main cause of death for lung cancer patients. The ex vivo 4D acellular lung model has been shown to mimic this metastatic process. However, the main concern is the model's lack of cellular components of the tumor's microenvironment. In this study, we aim to determine if the intact lung microenvironment will still allow lung cancer metastasis to form. METHODS: We harvested a heart-lung block from a rat and placed it in a bioreactor after cannulating the pulmonary artery, trachea and tying the right main bronchus for 10-15 days without any tumor cells as a control group or with NSCLC (A549, H1299 or H460), SCLC (H69, H446 or SHP77) or breast cancer cell lines (MCF7 or MDAMB231) through the trachea. We performed lobectomy, H&E staining and IHC for human mitochondria to determine the primary tumor's growth and formation of metastatic lesions. In addition, we isolated circulating tumor cells (CTC) from the model seeded with GFP tagged cells. RESULTS: In the control group, no gross tumor nodules were found, H&E staining showed hyperplastic cells and IHC showed no staining for human mitochondria. All of the models seeded with cancer cell lines formed gross primary tumor nodules that had microscopic characteristics of human cancer cells on H&E staining with IHC showing staining for human mitochondria. CTC were isolated for those cells labeled with GFP and they were viable in culture. Finally, all cell lines formed metastatic lesions with cells stained for human mitochondria. CONCLUSION: The cellular ex vivo 4D model shows that human cancer cells can form a primary tumor, CTC and metastatic lesions in an intact cellular environment. This study suggests that the natural matrix scaffold is the only necessary component to drive metastatic progression and that cellular components play a role in modulating tumor progression.

Breast cancer cells form primary tumors on ex vivo four-dimensional lung model.

BACKGROUND: Breast cancer mortality is most common in cancer in women, and there are no ex vivo models that can capture the primary growth of tumor with fidelity to the in vivo tumor growth. In this study, we grew human breast cancer cell lines in an acellular lung matrix of the ex vivo four-dimensional lung model to determine if they form primary tumor and the extent to which they mimic the histology and characteristics of the human tumors. MATERIALS AND METHODS: Rat lungs were harvested, decellularized, and placed in a bioreactor. To study the primary tumor growth, we seeded the lung via the trachea with human breast cancer cells SUM159, MCF7, or MDMB231 and perfused the pulmonary artery with oxygenated media. Lobectomies were performed and processed for hematoxylin and eosin, Ki-67, caspase-3, estrogen receptor, and progesterone receptor antibodies. RESULTS: All three cell lines grew in the ex vivo four-dimensional model and formed perfusable tumor nodules with similar histology and morphology as the primary tumors. SUM159 and MDAMB231 showed higher proliferation and apoptotic indices than MCF7. In addition, MCF7 retained its estrogen receptor and progesterone receptor positivity, whereas SUM159 and MDAMB 231 did not have any staining. CONCLUSIONS: Overall, our study showed that human breast cancer cells can be grown on the ex vivo four-dimensional lung model, which then form primary tumor nodules that mimic the morphology and histology of the original tumor.

Management of asymptomatic pulmonary vein aneurysm.

Aneurysm of a pulmonary vein is a rare vascular anomaly that is usually discovered incidentally as a pulmonary nodule or mediastinal mass. Most patients do not have any symptoms but some patients can present with dyspnea, hemoptysis, or cerebral thromboembolism. Proper diagnosis is crucial as to avoid unnecessary testing or surgical procedures. We highlight a case of an asymptomatic 59-year-old female with a pulmonary vein aneurysm presenting as a 1.5 cm right infrahilar nodule on contrast-enhanced CT during evaluation for acute cholecystitis. Further investigation with MRA revealed that it was vascular in nature, and pulmonary angiography showed dilation of the right inferior pulmonary vein with no communication to the pulmonary artery. On serial imaging, there has been no change in the size of the aneurysm. A small non-enlarging pulmonary vein aneurysm should be managed expectantly.