Osteosarcoma-Derived Extracellular Vesicles Induce Lung Fibroblast Reprogramming.

Tumor-secreted extracellular vesicles (EVs) have been identified as mediators of cancer-host intercellular communication and shown to support pre-metastatic niche formation by modulating stromal cells at future metastatic sites. While osteosarcoma, the most common primary malignant bone tumor in children and adolescents, has a high propensity for pulmonary metastases, the interaction of osteosarcoma cells with resident lung cells remains poorly understood. Here, we deliver foundational in vitro evidence that osteosarcoma cell-derived EVs drive myofibroblast/cancer-associated fibroblast differentiation. Human lung fibroblasts displayed increased invasive competence, in addition to increased α-smooth muscle actin expression and fibronectin production upon EV treatment. Furthermore, we demonstrate, through the use of transforming growth factor beta receptor 1 (TGFBR1) inhibitors and CRISPR-Cas9-mediated knockouts, that TGFß1 present in osteosarcoma cell-derived EVs is responsible for lung fibroblast differentiation. Overall, our study highlights osteosarcoma-derived EVs as novel regulators of lung fibroblast activation and provides mechanistic insight into how osteosarcoma cells can modulate distant cells to potentially support metastatic progression.

Fascin-1 enhances experimental osteosarcoma tumor formation and metastasis and is related to poor patient outcome.

BACKGROUND: Fascin-1, a prominent actin-bundling protein, is found to be upregulated in several human carcinomas. While it is accepted that Fascin-1 expression correlates with poor clinical outcome and decreased survival in various carcinomas, its role in sarcoma such as osteosarcoma (OS) remains unknown. In the present study, we evaluated the prognostic value and biological relevance of Fascin-1 in OS. METHODS: The correlation between Fascin-1 expression and the outcome of OS patients was determined by immunohistochemistry analysis of Fascin-1 expression in a tissue microarray of OS tissue specimens collected during primary tumor resection. To examine the effect of Fascin-1, shRNA and overexpression technology to alter Fascin-1 levels in OS cells were used in cellular assays as well as in intratibial xenograft OS models in SCID mice. RESULTS: Kaplan-Meier survival analysis of Fascin-1 expression in OS tumor specimens revealed a direct relationship between Fascin-1 expression and poor patient survival. Furthermore, overexpression of Fascin-1 in OS cells significantly increased their migratory capacity as well as the activity of the matrix metalloprotease MMP-9, known to be critical for the execution of metastasis. Finally, using relevant xenograft mouse models, orthotopic intratibial transplantation of two different OS cell lines overexpressing Fascin-1 promoted tumor growth and lung metastasis. CONCLUSIONS: Collectively, our findings demonstrate for the first time that Fascin-1 has considerable potential as a novel prognostic biomarker in OS, and suggest that targeting of Fascin-1 might be a new anti-metastatic strategy in OS patient treatment.

Exercise right heart catheterisation before and after pulmonary endarterectomy in patients with chronic thromboembolic disease.

Symptomatic patients with chronic thromboembolic disease (CTED) without pulmonary hypertension often show an excessive increase in mean pulmonary arterial pressure (MPAP) during exercise.We report on the impact of pulmonary endarterectomy (PEA) on pulmonary haemodynamics in a prospective series of 32 consecutive CTED patients who underwent PEA. All patients had a comprehensive diagnostic work-up including right heart catheterisation at baseline and 12 months after PEA. Furthermore, in 12 patients exercise right heart catheterisation was performed before and after PEA.After PEA, MPAP was lower at rest (20±3 versus 17±3 mmHg; p=0.008) and during maximal exercise (39±8 versus 31±6 mmHg; p=0.016). The mean total pulmonary resistance (TPR) decreased from 3.6±0.8 Wood Units (WU) pre-operatively to 2.7±0.7 WU 1 year after PEA (p=0.004) and the mean slope of the MPAP/cardiac output (CO) relationship decreased from 3.6±1.0 to 2.3±0.8 WU (p=0.002). Peak oxygen uptake increased from 1.2±0.4 to 1.5±0.3 L·min-1 (p=0.014) and ventilatory equivalents of carbon dioxide decreased from 39±2 to 30±2 (p=0.002). There was a significant improvement in quality of life assessed by the Cambridge Pulmonary Hypertension Outcome Review questionnaire.In CTED patients, PEA resulted in haemodynamic and clinical improvements. The means of TPR and MPAP/CO slopes decreased to <3.0 WU.

The effective systematic heparin pre-treatment on thrombus formation on pulmonary artery catheter tips during pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: a randomized, double-blind study.

Pulmonary artery (PA) catheters are routinely used for hemodynamic management in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy (PEA). Tip-associated thrombi are frequently detected and might increase the peri-operative risk in these patients. The aim of the study was to investigate the effects of low-dose heparinization before the insertion of the PA catheter on thrombus formation and thrombus weight during PEA surgery. From September 2013 to February 2015, 60 CTEPH patients undergoing PEA were included in the study and randomized into two groups of 30 patients each, including a heparin group (heparin bolus (70 IU per kg body weight) administration before PA catheter insertion) and a control group (pretreatment with placebo). During the PEA procedure the distal part of the PA catheter was drawn out of the PA and thrombus presence and weight were recorded. There were no significant differences in baseline characteristics between the two groups. Twelve patients (20%) had thrombophilic disorders. In the control group, thrombi were detected in 17 patients (57%) with a median thrombus weight of 27 mg (IQR 41). In the heparin group, tip-associated thrombi were found in five patients (17%) with a median weight of 12 mg (IQR 7). There were no bleeding complications in either group. This study demonstrates a high risk of PA catheter-related thrombi in patients with CTEPH. Prophylactic administration of low-dose heparin reduces thrombus formation and thrombus weight without an increased rate of bleeding complications.

Matrix Metalloproteinase 1 promotes tumor formation and lung metastasis in an intratibial injection osteosarcoma mouse model.

Proteolytic degradation of the extracellular matrix (ECM) is an important process during tumor invasion. Matrix Metalloproteinase 1 (MMP-1) is one of the proteases that degrade collagen type I, a major component of bone ECM. In the present study, the biological relevance of MMP-1 in osteosarcoma (OS) tumor growth and metastasis was investigated in vitro and in vivo. Human OS cells in primary culture expressed MMP-1 encoding mRNA at considerably higher levels than normal human bone cells. In addition, MMP-1 mRNA and protein expression in the highly metastatic human osteosarcoma 143-B cell line was remarkably higher than in the non-metastatic parental HOS cell line. Stable shRNA-mediated downregulation of MMP-1 in 143-B cells impaired adhesion to collagen I and anchorage-independent growth, reflected by a reduced ability to grow in soft agar. Upon intratibial injection into SCID mice, 143-B cells with shRNA-downregulated MMP-1 expression formed smaller primary tumors and significantly lower numbers of lung micro- and macrometastases than control cells. Conversely, HOS cells stably overexpressing MMP-1 showed an enhanced adhesion capability to collagen I and accelerated anchorage-independent growth compared to empty vector-transduced control cells. Furthermore, and most importantly, individual MMP-1 overexpression in HOS cells enabled the formation of osteolytic primary tumors and lung metastasis while the HOS control cells did not develop any tumors or metastases after intratibial injection. The findings of the present study reveal an important role of MMP-1 in OS primary tumor and metastasis formation to the lung, the major organ of OS metastasis.

Caprin-1, a novel Cyr61-interacting protein, promotes osteosarcoma tumor growth and lung metastasis in mice.

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. More than 30% of patients develop lung metastasis, which is the leading cause of mortality. Recently, the extracellular matrix protein Cyr61 has been recognized as a malignancy promoting protein in OS mouse model with prognostic potential in human OS. In this study, we aimed at the identification of novel Cyr61-interacting proteins. Here we report that Cyr61 associates with Caprin-1, and confocal microscopy showed that stable ectopic expression of Caprin-1 leads to the formation of stress granules containing Caprin-1 and Cyr61, confers resistance to cisplatin-induced apoptosis, and resulted in constitutive phosphorylation of Akt and ERK1/2. Importantly, ectopic expression of Caprin-1 dramatically enhanced primary tumor growth, remarkably increased lung metastatic load in a SCID intratibial OS mouse model, and decreased significantly (p<0.0018) the survival of the mice. Although Caprin-1 expression, evaluated with a tissue microarray including samples from 59 OS patients, failed to be an independent predictor for the patients' outcome in this limited cohort of patients, increased Caprin-1 expression indicated a tendency to shortened overall survival, and more strikingly, Cyr61/Caprin-1 co-expression was associated with worse survival than that observed for patients with tumors expressing either Cyr61 or Caprin-1 alone or none of these proteins. The findings imply that Caprin-1 may have a metastasis promoting role in OS and show that through resistance to apoptosis and via the activation of Akt and ERK1/2 pathways, Caprin-1 is significantly involved in the development of OS metastasis.

Single-center experience with extracorporeal life support in 103 nonpostcardiotomy patients.

Extracorporeal membrane oxygenation (ECMO) has been successfully used to support patients with cardiac arrest failing to respond to conventional cardiopulmonary resuscitation (CPR). Preimplant factors being indicative for success are unknown up to now. The study describes single center experience with special focus on differences between survivors and nonsurvivors. Between 2002 and 2009, 103 patients were supported within the scope of CPR by means of ECMO. Besides primary diagnosis, duration, and outcome, pH, lactate, mean arterial pressure, aspartate aminotransferase, bilirubin, catecholamine dosage, and oxygenation ratio before ECMO, after 2 h, 1 day, and at explantation were analyzed. One hundred three patients (51.2 ± 16 years, 35 women, 68 men) were analyzed. Primary cardiac failure led to CPR in 54%. Duration of support was 4.8 ± 0.6 days. Twenty-nine (28.1%) patients survived to hospital discharge. On ECMO support, pH, lactate, and mean arterial pressure improved significantly. Catecholamine dosage was significantly reduced after ECMO implantation. Demographic data and primary diagnosis revealed no significant influence on outcome. pH, lactate, creatinine, and bilirubin differed significantly between survivors and nonsurvivors in the course of ECMO support. ECMO support during CPR reliably improves the circulatory and respiratory situation. Considering observed survival critical patient selection is mandatory. Although there are several significant differences between surviving patients and patients with fatal outcome, patient selection turns out to be difficult as clinically relevant factors show only limited predictive value. Future research should focus on better defining a population that may be best of all suited for the use of ECMO support in CPR.

The antineoplastic antibiotic taurolidine promotes lung and liver metastasis in two syngeneic osteosarcoma mouse models and exhibits severe liver toxicity.

Osteosarcoma (OS) is the most frequent primary bone tumor. Despite multiagent neoadjuvant chemotherapy, patients with metastatic disease have a poor prognosis. Moreover, currently used chemotherapeutics have severe toxic side effects. Thus, novel agents with improved antimetastatic activity and reduced toxicity are needed. Taurolidine, a broad-spectrum antimicrobial, has recently been shown to have antineoplastic properties against a variety of tumors and low systemic toxicity. Consequently, we investigated in our study the antineoplastic potential of taurolidine against OS in two different mouse models. Although both OS cell lines, K7M2 and LM8, were sensitive for the compound in vitro, intraperitoneal application of taurolidine failed to inhibit primary tumor growth. Moreover, it enhanced the metastatic load in both models 1.7- to 20-fold and caused severe liver deformations and up to 40% mortality. Thus, systemic toxicity was further investigated in tumor-free mice histologically, by electron microscopy and by measurements of representative liver enzymes. Taurolidine dose-dependent fibrous thickening of the liver capsule and adhesions and atrophies of the liver lobes were comparable in healthy and tumor-bearing mice. Liver toxicity was further indicated by up to eightfold elevated levels of the liver enzymes alanine transaminase, aspartate transaminase and GLDH in the circulation. Ultrastructural analysis of affected liver tissue showed swollen mitochondria with cristolysis and numerous lipid vacuoles in the cytoplasm of hepatocytes. The findings of our study question the applicability of taurolidine for OS treatment and may suggest the need for caution regarding the widespread clinical use of taurolidine as an antineoplastic agent.

Antimetastatic activity of honokiol in osteosarcoma.

BACKGROUND: Metastasizing osteosarcoma has a mean 5-year survival rate of only 20% to 30%. Therefore, novel chemotherapeutics for more effective treatment of this disease are required. METHODS: The antineoplastic activity of honokiol, which was demonstrated previously in numerous malignancies, was studied in vivo in C3H mice subcutaneously injected with syngeneic ß-galactosidase bacterial gene (lacZ)-expressing LM8 osteosarcoma (LM8-lacZ) cells. In vitro cytotoxic effects of honokiol were investigated in 8 human and 2 murine osteosarcoma cell lines with different in vivo metastatic potential. RESULTS: Seven days after subcutaneous flank injection of LM8-lacZ cells, daily intraperitoneal treatment of mice with 150 mg/kg honokiol reduced the number of micrometastases in the lung by 41% and reduced the number of macrometastases in the lung and liver by 69% and 80%, respectively, compared with control. Primary tumor growth was not inhibited. In osteosarcoma cell lines, honokiol inhibited the metabolic activity with a half-maximal concentration (IC(50) ) between 8.0 µg/mL and 16 µg/mL. Cyclosporin A partially reversed the inhibition of metabolic activity in LM8-lacZ cells. Cell proliferation and wound healing migration of LM8-lacZ cells were inhibited by honokiol with an IC(50) between 5.0 µg/mL and 10 µg/mL. Higher concentrations caused rapid cell death, which was distinct from necrosis, apoptosis, or autophagy but was associated with swelling of the endoplasmic reticulum, cytoplasmic vacuolation, and morphologically altered mitochondria. CONCLUSIONS: Honokiol exhibited prominent antimetastatic activity in experimental osteosarcoma and caused rapid cell death in vitro that was unrelated to necrosis, apoptosis, or autophagy. The authors concluded that honokiol has considerable potential for the treatment of metastasizing osteosarcoma.

Shear-stress sensing by PIEZO1 regulates tendon stiffness in rodents and influences jumping performance in humans.

Athletic performance relies on tendons, which enable movement by transferring forces from muscles to the skeleton. Yet, how load-bearing structures in tendons sense and adapt to physical demands is not understood. Here, by performing calcium (Ca2+) imaging in mechanically loaded tendon explants from rats and in primary tendon cells from rats and humans, we show that tenocytes detect mechanical forces through the mechanosensitive ion channel PIEZO1, which senses shear stresses induced by collagen-fibre sliding. Through tenocyte-targeted loss-of-function and gain-of-function experiments in rodents, we show that reduced PIEZO1 activity decreased tendon stiffness and that elevated PIEZO1 mechanosignalling increased tendon stiffness and strength, seemingly through upregulated collagen cross-linking. We also show that humans carrying the PIEZO1 E756del gain-of-function mutation display a 13.2% average increase in normalized jumping height, presumably due to a higher rate of force generation or to the release of a larger amount of stored elastic energy. Further understanding of the PIEZO1-mediated mechanoregulation of tendon stiffness should aid research on musculoskeletal medicine and on sports performance.

Determinants of cerebral oximetry in patients undergoing off-pump coronary artery bypass grafting: an observational study.

BACKGROUND AND OBJECTIVE: The present study investigated whether positioning of the heart during off-pump coronary artery bypass grafting leads to changes in regional cerebral oxygen saturation measured by near infrared spectroscopy. METHODS: In 35 consecutive patients undergoing elective off-pump coronary artery bypass grafting, cerebral oxygen saturation was measured by near infrared spectroscopy. A 20% decrease from baseline values was considered to be cerebral hypoperfusion. Mean arterial pressure, cardiac index, arterial carbon dioxide partial pressure, central venous pressure, haemoglobin concentration, and body temperature were determined simultaneously. Each value was recorded at the following time points: at baseline; after positioning the heart for distal anastomoses of the left anterior descending artery, the circumflex, and the right coronary artery; after repositioning the heart; and after chest closure. Significant changes in each parameter from baseline were detected using repeated-measures analysis of variance. Determinants of cerebral oxygen saturation during surgery were analysed by means of generalized estimation equations. RESULTS: Cerebral oxygen saturation remained constant during grafting of the left anterior descending artery and decreased significantly during grafting of the circumflex (P = 0.001) and the right coronary artery (P < 0.001). Cerebral hypoperfusion was found in seven (20%) patients. Changes in haemoglobin concentration (P = 0.014), arterial CO2 partial pressure (P = 0.001), cardiac output (P < 0.001), and central venous pressure (P = 0.014) determined alterations in cerebral oxygen saturation. CONCLUSION: Positioning of the heart during off-pump coronary artery bypass grafting leads to a decrease in regional cerebral oxygen saturation. This decrease is associated with changes in cardiac output, haemoglobin concentration, arterial CO2 partial pressure, and central venous pressure.

Exploring the Role of Osteosarcoma-Derived Extracellular Vesicles in Pre-Metastatic Niche Formation and Metastasis in the 143-B Xenograft Mouse Osteosarcoma Model.

The pre-metastatic niche (PMN) is a tumor-driven microenvironment in distant organs that can foster and support the survival and growth of disseminated tumor cells. This facilitates the establishment of secondary lesions that eventually form overt metastasis, the main cause of cancer-related death. In recent years, tumor-derived extracellular-vesicles (EVs) have emerged as potentially key drivers of the PMN. The role of the PMN in osteosarcoma metastasis is poorly understood and the potential contribution of osteosarcoma cell-derived EVs to PMN formation has not been investigated so far. Here, we characterize pulmonary PMN development using the spontaneously metastasizing 143-B xenograft osteosarcoma mouse model. We demonstrate the accumulation of CD11b+ myeloid cells in the pre-metastatic lungs of tumor-bearing mice. We also establish that highly metastatic 143-B and poorly metastatic SAOS-2 osteosarcoma cell-derived EV education in naïve mice can recapitulate the recruitment of myeloid cells to the lungs. Surprisingly, despite EV-induced myeloid cell infiltration in the pre-metastatic lungs, 143-B and SAOS-2 EVs do not contribute towards the 143-B metastatic burden in the context of both spontaneous as well as experimental metastasis in severe-combined immunodeficient (SCID) mice. Taken together, OS-derived EVs alone may not be able to form a functional PMN, and may perhaps require a combination of tumor-secreted factors along with EVs to do so. Additionally, our study gives a valuable insight into the PMN complexity by providing the transcriptomic signature of the premetastatic lungs in an osteosarcoma xenograft model for the first time. In conclusion, identification of regulators of cellular and molecular changes in the pre-metastatic lungs might lead to the development of a combination therapies in the future that interrupt PMN formation and combat osteosarcoma metastasis.

TRPV4 Inhibition and CRISPR-Cas9 Knockout Reduce Inflammation Induced by Hyperphysiological Stretching in Human Annulus Fibrosus Cells.

Mechanical loading and inflammation interact to cause degenerative disc disease and low back pain (LBP). However, the underlying mechanosensing and mechanotransductive pathways are poorly understood. This results in untargeted pharmacological treatments that do not take the mechanical aspect of LBP into account. We investigated the role of the mechanosensitive ion channel TRPV4 in stretch-induced inflammation in human annulus fibrosus (AF) cells. The cells were cyclically stretched to 20% hyperphysiological strain. TRPV4 was either inhibited with the selective TRPV4 antagonist GSK2193874 or knocked out (KO) via CRISPR-Cas9 gene editing. The gene expression, inflammatory mediator release and MAPK pathway activation were analyzed. Hyperphysiological cyclic stretching significantly increased the IL6, IL8, and COX2 mRNA, PGE2 release, and activated p38 MAPK. The TRPV4 pharmacological inhibition significantly attenuated these effects. TRPV4 KO further prevented the stretch-induced upregulation of IL8 mRNA and reduced IL6 and IL8 release, thus supporting the inhibition data. We provide novel evidence that TRPV4 transduces hyperphysiological mechanical signals into inflammatory responses in human AF cells, possibly via p38. Additionally, we show for the first time the successful gene editing of human AF cells via CRISPR-Cas9. The pharmacological inhibition or CRISPR-based targeting of TRPV4 may constitute a potential therapeutic strategy to tackle discogenic LBP in patients with AF injury.

The miR-143/145 Cluster, a Novel Diagnostic Biomarker in Chondrosarcoma, Acts as a Tumor Suppressor and Directly Inhibits Fascin-1.

Chondrosarcoma is the second most frequent bone sarcoma. Due to the inherent chemotherapy and radiotherapy resistance and absence of known therapeutic targets, clinical management is limited to surgical resection. Consequently, patients with advanced disease face a poor prognosis. Hence, elucidating regulatory networks governing chondrosarcoma pathogenesis is vital for development of effective therapeutic strategies. Here, miRNA and mRNA next generation sequencing of different subtypes of human chondrogenic tumors in combination with in silico bioinformatics tools were performed with the aim to identify key molecular factors. We identified miR-143/145 cluster levels to inversely correlate with tumor grade. This deregulation was echoed in the miRNA plasma levels of patients and we provided the first evidence that circulating miR-145 is a potential noninvasive diagnostic biomarker and can be valuable as an indicator to improve the currently challenging diagnosis of cartilaginous bone tumors. Additionally, artificial upregulation of both miRNAs impelled a potent tumor suppressor effect in vitro and in vivo in an orthotopic xenograft mouse model. A combined in silico/sequencing approach revealed FSCN1 as a direct target of miR-143/145, and its depletion phenotypically resembled miR-143/145 upregulation in vitro. Last, FSCN1 is a malignancy-promoting factor associated with aggressive chondrosarcoma progression. Our findings underscore miR-143/145/FSCN1 as important players in chondrosarcoma and may potentially open new avenues for specific therapeutic intervention options. © 2020 American Society for Bone and Mineral Research.

Pumpless extracorporeal interventional lung assist in patients with acute respiratory distress syndrome: a prospective pilot study.

INTRODUCTION: Pumpless interventional lung assist (iLA) is used in patients with acute respiratory distress syndrome (ARDS) aimed at improving extracorporeal gas exchange with a membrane integrated in a passive arteriovenous shunt. In previous studies, feasibility and safety of the iLA system was demonstrated, but no survival benefit was observed. In the present pilot study we tested the hypothesis that timely initiation of iLA using clear algorithms and an improved cannulation technique will positively influence complication rates and management of lung protective ventilation. METHODS: iLA was implemented in 51 patients from multiple aetiologies meeting ARDS-criteria (American-European Consensus) for more than 12 hours. Initiation of iLA followed an algorithm for screening, careful evaluation and insertion technique. Patients with cardiac insufficiency or severe peripheral vascular disease were not considered suitable for iLA. Arterial and venous cannulae were inserted using a new strategy (ultrasound evaluation of vessels by an experienced team, using cannulae of reduced diameter). The incidence of complications and the effects on tidal volumes and inspiratory plateau pressures were primary outcome parameters, while oxygenation improvement and carbon dioxide removal capabilities were secondary study parameters. RESULTS: Initiation of iLA resulted in a marked removal in arterial carbon dioxide allowing a rapid reduction in tidal volume (

A new miniaturized system for extracorporeal membrane oxygenation in adult respiratory failure.

INTRODUCTION: Mortality of severe acute respiratory distress syndrome in adults is still unacceptably high. Extracorporeal membrane oxygenation (ECMO) could represent an important treatment option, if complications were reduced by new technical developments. METHODS: Efficiency, side effects and outcome of treatment with a new miniaturized device for veno-venous extracorporeal gas transfer were analysed in 60 consecutive patients with life-threatening respiratory failure. RESULTS: A rapid increase of partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) from 64 (48 to 86) mmHg to 120 (84 to 171) mmHg and a decrease of PaCO2 from 63 (50 to 80) mmHg to 33 (29 to 39) mmHg were observed after start of the extracorporeal support (P < 0.001). Gas exchange capacity of the device averaged 155 (116 to 182) mL/min for oxygen and 210 (164 to 251) mL/min for carbon dioxide. Ventilatory parameters were reduced to a highly protective mode, allowing a fast reduction of tidal volume from 495 (401 to 570) mL to 336 (292 to 404) mL (P < 0.001) and of peak inspiratory pressure from 36 (32 to 40) cmH2O to 31 (28 to 35) cmH2O (P < 0.001). Transfusion requirements averaged 0.8 (0.4 to 1.8) units of red blood cells per day. Sixty-two percent of patients were weaned from the extracorporeal system, and 45% survived to discharge. CONCLUSIONS: Veno-venous extracorporeal membrane oxygenation with a new miniaturized device supports gas transfer effectively, allows for highly protective ventilation and is very reliable. Modern ECMO technology extends treatment opportunities in severe lung failure.

Emergency use of extracorporeal membrane oxygenation in cardiopulmonary failure.

Severe pulmonary and cardiopulmonary failure resistant to critical care treatment leads to hypoxemia and hypoxia-dependent organ failure. New treatment options for cardiopulmonary failure are necessary even for patients in outlying medical facilities. If these patients are in need of specialized center treatment, additional emergency medical service has to be carried out quick and safely. We describe our experiences with a pumpless extracorporeal lung assist (PECLA/iLA) for out-of-center emergency treatment of hypercapnic respiratory failure and the use of a newly developed hand-held extracorporeal membrane oxygenation (ECMO) system in cardiac, pulmonary, and cardiopulmonary failure (EMERGENCY-LIFE Support System, ELS System, MAQUET Cardiopulmonary AG, Hechingen, Germany). Between March 2000 and April 2009, we used the PECLA System (n = 20) and the ELS System (n = 33) in adult patients. Cannulation was employed using percutaneous vessel access. The new hand-held ELS System consists of a centrifugal pump and a membrane oxygenator, both mounted on a special holder system for storing on a standard patient gurney for air or ground ambulance transfer. Bedside cannulation processes were uneventful. The PECLA System resulted in sufficient CO(2) removal. In all ECMO patients, oxygen delivery and systemic blood flow could be restored and vasopressor support was markedly down. Hospital survival rate in the PECLA group was 50%, and 61% in the ECMO group. Out-of-center emergency treatment of hypercapnic pulmonary failure with pumpless extracorporeal gas exchange and treatment of cardiac, pulmonary, and cardiopulmonary failure with this new hand-held ECMO device is safe and highlyeffective. Patient outcome in cardiopulmonary organ failure could be improved.

Extracorporeal circulatory systems in the interhospital transfer of critically ill patients: experience of a single institution.

BACKGROUND AND OBJECTIVES: Critically ill patients with acute circulatory failure cannot be moved to other institutions unless stabilized by mechanical support systems. Extracorporeal heart and lung assist systems are increasingly used as a bridge to end-organ recovery or transplantation, and as an ultimate rescue tool in cardiopulmonary resuscitation. PATIENTS AND METHODS: From July 2001 to April 2008, we had 38 requests for extracorporeal support for interhospital transfer carried out by the air medical service. Respiratory failure was present in 29 patients, who were provided with pumpless extracorporeal lung assist (PECLA) or veno-venous extracorporeal membrane oxygenation (ECMO). Cardiac failure dominated in 9 patients, who underwent implantation of extracorporeal life support (ECLS). Underlying diseases were acute respiratory distress syndrome in 15 patients, pneumonia in 7, prior lung transplant status in 4, cardiogenic shock in 7, and septic shock in 4. RESULTS: All assist systems were connected via peripheral vessels by the Seldinger technique. Transport was uneventful in all cases with no technical failures. On arrival at the specialized care hospital, two patients had leg ischemia and underwent relocation of the arterial cannula. After a mean (SD) support of 5.1 (3.0) days for PECLA, 3.5 (2.9) days for ECLS, and 7.3 (5.8) days for ECMO, 60%, 66%, and 66% of patients, respectively, could be successfully weaned from the systems. Discharge rates were 45% for PECLA, 44% for ECLS, and 56% for ECMO. CONCLUSION: Our experience proves that minimized extracorporeal assist devices allow safe assistance of patients with isolated or combined heart and lung failure in need of interhospital transfer. Critically ill patients get a chance to reach a center of maximum medical care.

Efficient inhibition of intra-peritoneal tumor growth and dissemination of human ovarian carcinoma cells in nude mice by anti-L1-cell adhesion molecule monoclonal antibody treatment.

The L1 cell adhesion molecule is implicated in the control of proliferation, migration, and invasion of several tumor cell types in vitro. Recently, L1 overexpression was found to correlate with tumor progression of ovarian carcinoma, one of the most common causes of cancer-related deaths in gynecologic malignant diseases. To evaluate L1 as a potential target for ovarian cancer therapy, we investigated the effects of anti-L1 monoclonal antibodies (chCE7 and L1-11A) on proliferation and migration of L1-positive human SKOV3ip ovarian carcinoma cells in vitro and the therapeutic efficacy of L1-11A against i.p. SKOV3ip tumor growth in nude mice. In vitro, both anti-L1 antibodies efficiently inhibited the proliferation of SKOV3ip cells as well as other L1-expressing tumor cell lines (renal carcinoma, neuroblastoma, and colon carcinoma). On two cell lines, hyper-cross-linking of L1-11A with a secondary antibody was necessary for significant inhibition of proliferation, indicating that cross-linking of L1 is required for the antiproliferative effect. L1-negative prostate carcinoma cells were not influenced by antibody treatment. Biweekly treatment of ovarian carcinoma-bearing mice with L1-11A led to a dose-dependent and significant reduction of tumor burden (up to -63.5%) and ascites formation (up to -75%). This effect was associated with reduced proliferation within the tumors. L1-directed antibody-based inhibition of peritoneal growth and dissemination of human ovarian carcinoma cells represents important proof-of-principle for the development of a new therapy against one of the leading gynecologic malignant diseases.

Short-term venoarterial extracorporeal membrane oxygenation for massive endobronchial hemorrhage after pulmonary endarterectomy.

OBJECTIVES: Pulmonary endarterectomy (PEA) is the only curative treatment option for patients with chronic thromboembolic pulmonary hypertension. Massive endobronchial bleeding that precludes weaning from cardiopulmonary bypass is an often-fatal complication of PEA. The aim of this study was to determine whether short-term extracorporeal membrane oxygenation (ECMO) is a safe and feasible procedure in patients with severe endobronchial bleeding. METHODS: From January 2014 to December 2016, 396 patients (mean age 60 ± 18 years, 54.5% male) underwent PEA in our department. Patients with severe endobronchial hemorrhage at the time of weaning from cardiopulmonary bypass (CPB) were switched to a heparin-coated venoarterial ECMO circuit. After full-dose protamine administration to restore normal coagulation, weaning from ECMO was attempted in the operating room. RESULTS: In-hospital mortality was 2.3% (9/396 patients). Eight patients (2.0%) developed severe endobronchial bleeding classified as diffuse (n = 6) or localized (n = 2) by bronchoscopy. After reinstitution of CPB and subsequent switch to ECMO, the mean duration of ECMO support was 49 ± 13 minutes, and all 8 patients were weaned successfully from ECMO in the operating theater without further signs of endobronchial bleeding. One patient needed venovenous ECMO support for poor oxygenation 6 hours after surgery. Seven patients were discharged after a prolonged postoperative stay of 17.6 ± 4.1 days. One patient died. This new concept significantly reduced mortality compared with previous (2009-2013) ECMO support (P = .0406). CONCLUSIONS: For patients with massive endobronchial bleeding after PEA, the intraoperative switch from CPB to venoarterial ECMO support with full-dose protamine administration is a new and potentially life-saving treatment concept.