5-Fluorouracil induced extravasation injury.

Antineoplastic drugs based on their ability to cause local damage are classified as irritants, vesicants, and non-vesicants. Previous literature has reported higher rate of vesicants induced extravasation (EV) compared to irritants. We report the first case of irritant, 5-fluorouracil causing grade III EV in 55-year-old woman. The patient was diagnosed with esophageal squamous cell carcinoma. Docetaxel, Cisplatin, and 5-Fluorouracil (DCF) chemotherapy regimen was planned and administered through peripheral venous access. Patient experienced grade 3 extravasation in her 3rd cycle following 5-fluorouracil (5-FU) administration. The suspected drug was withdrawn immediately and discontinued from the 4th cycle of the regimen. The patient completely recovered from the symptoms of pain and erythema in the next cycle and care was taken not to infuse drug in the same site again. Since there is no appropriate antidote available to manage this condition, measures need to be taken to identify the predisposing factors for EV and prevent them.

[A woman with a swollen upper arm]. / Een vrouw met een gezwollen bovenarm.

A 74-year-old female patient presented at the emergency department with a swollen upper arm after a CT-scan. X-ray showed extensive extravasation with iodinated contrast media. Extravasations of high volume or high osmolality can lead to severe tissue damage. Early recognition and treatment is important, since it could prevent further injury.

Human umbilical cord blood cells restore vascular integrity in injured rat brain and modulate inflammation in vitro.

Aim: Traumatic brain injury is a complex condition consisting of a mechanical injury with neurovascular disruption and inflammation with limited clinical interventions available. A growing number of studies report systemic delivery of human umbilical cord blood (HUCB) as a therapy for neural injuries. Materials & methods: HUCB cells from five donors were tested to improve blood-brain barrier integrity in a traumatic brain injury rat model at a dose of 2.5 × 107 cells/kg at 24 or 72 h postinjury and for immunomodulatory activity in vitro. Results & Conclusion: We observed that cells delivered 72 h postinjury significantly restored blood-brain barrier integrity. HUCB cells reduced the amount of TNF-α and IFN-γ released by activated primary rat splenocytes, which correlated with the expression of COX2 and IDO1.

Nanoparticles promote in vivo breast cancer cell intravasation and extravasation by inducing endothelial leakiness.

While most cancer nanomedicine is designed to eliminate cancer, the nanomaterial per se can lead to the formation of micrometre-sized gaps in the blood vessel endothelial walls. Nanomaterials-induced endothelial leakiness (NanoEL) might favour intravasation of surviving cancer cells into the surrounding vasculature and subsequently extravasation, accelerating metastasis. Here, we show that nanoparticles induce endothelial leakiness through disruption of the VE-cadherin-VE-cadherin homophilic interactions at the adherens junction. We show that intravenously injected titanium dioxide, silica and gold nanoparticles significantly accelerate both intravasation and extravasation of breast cancer cells in animal models, increasing the extent of existing metastasis and promoting the appearance of new metastatic sites. Our results add to the understanding of the behaviour of nanoparticles in complex biological systems. The potential for NanoEL needs to be taken into consideration when designing future nanomedicines, especially nanomedicine to treat cancer.

Impact of contrast extravasation on computed tomography of the psoas major muscle in patients with blunt torso trauma.

BACKGROUND: The clinical significance of contrast extravasation (CE) on computed tomography (CT) of the psoas major muscle after blunt torso trauma and the optimal management of patients requiring transcatheter arterial embolization (TAE) of the lumbar artery have not been well elucidated. The aim of this study was to investigate the impact of CE on CT to determine the need for TAE of the lumbar artery. METHODS: We examined a single-center retrospective cohort of blunt torso trauma patients who underwent contrast-enhanced CT from 2008 to 2017. Basic demographics and clinical data were obtained, including the number of lumbar transverse process fractures (LTPFs) and maximum psoas major muscle hematoma (PMMH) size and ratio. Maximum PMMH size was analyzed by measuring the cross-sectional area of hematoma size at the level of CE. Psoas major muscle hematoma size ratio was obtained by dividing maximum PMMH size by psoas major muscle size of the unaffected side at the same slice level. RESULTS: A total of 762 patients were included. One hundred seventeen patients had LTPFs and/or PMMH. Of 117 patients, 25 had CE on CT of the psoas major muscle and had significantly higher rates of older age and severe injury compared with those without CE. Of the 25 patients with CE, 13 required TAE of the lumbar artery. Patients who required TAE had a significantly higher number of LTPFs (4 vs. 2, p = 0.011) and higher PMMH size ratio (2.10 vs. 1.32, p = 0.016). Psoas major muscle hematoma size ratio revealed moderate accuracy (area under the receiver operating characteristic curve, 0.782). CONCLUSIONS: Approximately half of the blunt torso trauma patients with CE on CT of the psoas major muscle will require TAE of the lumbar artery. Higher number of LTPFs and larger PMMH size can be a predictor of the need for TAE of the lumbar artery among patients with CE on CT. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Efficacy of Dehydrated Human Amniotic Membrane Allograft for the Treatment of Severe Extravasation Injuries in Preterm Neonates.

INTRODUCTION: A peripheral intravenous (PIV) catheter is placed in 60% to 70% of neonatal intensive care unit (NICU) infants. Extravasation injuries occur in 18% to 33%, with 70% in neonates < 27 weeks of gestational age. Despite such frequent use of PIV therapy, evidence on best practice, injury prevention, management, and treatment of extravasations is lacking. OBJECTIVE: This case series of 4 neonatal patients describes the experience and efficacy of using a dehydrated human amniotic membrane allograft (dHAMA) in the treatment of severe extravasation injuries. MATERIALS AND METHODS: The 4 preterm, critically ill neonates, all with stage 4 extravasations, were treated with 1 to 2 applications of the dHAMA to facilitate the repair process. Prior to treatments, standard of care included either enzymatic (collagenase ointment) or autolytic debridement (active Leptospermum honey) followed by mechanical debridement prior to allograft placement. RESULTS: The 4 full-thickness wounds exhibited recalcitrant healing. The dHAMA invigorated the wounds after standard management failed to induce repair. Application was easy and follow-up care was minimal. All wounds healed without contractures and with minimal soft scars and normal pigmentation at the 1- to 2-month follow-up visits. CONCLUSIONS: The dHAMA proved to be an effective, safe, and easy-to-apply treatment in this case series, leading to regeneration and healing of deep neonatal wounds associated with extravasations.

A modification and validation of quantitative morphometry classification system for osteoporotic vertebral compressive fractures in mainland Chinese.

This study described a modified quantitative morphometry (mQM) system adapted to specific reference values for Mainland Chinese population. The mQM system is validated using the Genant Semiquantative system and is sensitive for detecting vertebral height changes and predicting cement leakage after percutaneous kyphoplasty (PKP) in patients with osteoporotic vertebral compressive fracture (OVCF). INTRODUCTION: OVCF is a manifestation of osteoporosis. To improve clinical management of osteoporosis, the quantitative morphometry (QM) system has been widely used for the early diagnosis and precise classification of OVCF in developed countries. Here, we present an mQM system and validated its use in detecting OVCF in Mainland Chinese. METHODS: Using our mQM system, the pre- and post-operative values of vertebral heights were measured and evaluated in 309 Mainland Chinese who received percutaneous kyphoplasty (PKP) as OVCF treatment. Measurements and classification of fractures from the mQM system were validated by comparing to values obtained by the Genant semiquantative (SQ) method. Moreover, we evaluated the sensitivity of the mQM system by its ability to detect restoration of vertebral heights and predict cement leakage after PKP. RESULTS: The five classification of fractures, No deformity (ND), anterior wedge (AW), posterior wedge (PW), biconcavity (BC), and compression (CP), evaluated by the mQM method shared similar distribution characteristics compared to those obtained by the SQ method. In addition, mQM evaluation showed that the vertebra height of all fracture types showed significant restoration after PKP. The incidence of cement leakage was most common in CP (37.5%), followed by AW (31.6%), BC (26.5%), ND (23.7%), and PW (0.0%). CONCLUSIONS: Our mQM system is suitable for classification of fractures, detection of vertebral height restoration, and correlation of cement leakage after PKP in Mainland Chinese population.

Correlation Between Extravasation and Alterations of Cerebrovascular Laminin and ß-Dystroglycan Immunoreactivity Following Cryogenic Lesions in Rats.

The blood-brain barrier becomes "leaky" following lesions. Former studies revealed that following lesions the immunoreactivity of cerebrovascular laminin becomes detectable whereas that of ß-dystroglycan disappears. These alterations may be indicators of glio-vascular decoupling that may result in the impairment of the blood-brain-barrier. This study investigates correlation between the post-lesion extravasation and the above-mentioned immunohistochemical alterations. Following cryogenic lesions, the survival periods lasted 5, 10, 30 minutes, 1 or 12 hours, or 1 day. Some brains were fixed immediately post-lesion. Immunofluorescent reactions were performed in floating sections. The extravasation was detected with immunostaining for plasma fibronectin and rat immunoglobulins. When the survival period was 30 minutes or longer, the area of extravasation corresponded to the area of altered laminin and ß-dystroglycan immunoreactivities. Following immediate fixation some laminin immunoreactivity was already detected. The extravasation seemed to precede this early appearance of laminin immunoreactivity. The ß-dystroglycan immunoreactivity disappeared later. When the extravasation spread into the corpus callosum, vascular laminin immunoreactivity appeared but the ß-dystroglycan immunoreactivity persisted. It seems that extravasation separates the glial and vascular basal laminae, which results in the appearance of laminin immunoreactivity. The disappearance of ß-dystroglycan immunoreactivity is neither a condition nor an inevitable consequence of the 2 other phenomena.

Intravascular Survival and Extravasation of Tumor Cells.

Most metastasizing tumor cells reach distant sites by entering the circulatory system. Within the bloodstream, they are exposed to severe stress due to loss of adhesion to extracellular matrix, hemodynamic shear forces, and attacks of the immune system, and only a few cells manage to extravasate and to form metastases. We review the current understanding of the cellular and molecular mechanisms that allow tumor cells to survive in the intravascular environment and that mediate and promote tumor cell extravasation. As these processes are critical for the metastatic spread of tumor cells, we discuss implications for potential therapeutic approaches and future research.

Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts.

Efficient delivery of therapeutic nanoparticles (TNPs) to tumors is critical in improving efficacy, yet strategies that universally maximize tumoral targeting by TNP modification have been difficult to achieve in the clinic. Instead of focusing on TNP optimization, we show that the tumor microenvironment itself can be therapeutically primed to facilitate accumulation of multiple clinically relevant TNPs. Building on the recent finding that tumor-associated macrophages (TAM) can serve as nanoparticle drug depots, we demonstrate that local tumor irradiation substantially increases TAM relative to tumor cells and, thus, TNP delivery. High-resolution intravital imaging reveals that after radiation, TAM primarily accumulate adjacent to microvasculature, elicit dynamic bursts of extravasation, and subsequently enhance drug uptake in neighboring tumor cells. TAM depletion eliminates otherwise beneficial radiation effects on TNP accumulation and efficacy, and controls with unencapsulated drug show that radiation effects are more pronounced with TNPs. Priming with combined radiation and cyclophosphamide enhances vascular bursting and tumoral TNP concentration, in some cases leading to a sixfold increase of TNP accumulation in the tumor, reaching 6% of the injected dose per gram of tissue. Radiation therapy alters tumors for enhanced TNP delivery in a TAM-dependent fashion, and these observations have implications for the design of next-generation tumor-targeted nanomaterials and clinical trials for adjuvant strategies.

Tissue necrosis following extravasation of acyclovir in an adolescent: A case report.

OBJECTIVE: Extravasation of intravenously infused vesicant solutions is a common problem in medical practice, which can lead to severe and progressive tissue dysfunction, ranging from persistent tissue oedema and fibrosis to delayed tissue necrosis. Acyclovir is a known vesicant medication administrated in paediatric patients, which appears to irritate venous and soft tissue if extravasated. CASE REPORT: We present the first case involving the extravasation of intravenously infused acyclovir in a female adolescent patient, which caused tissue necrosis and left behind a residual scar lesion. Nursing and medical staff should be aware of the potential dermatological side effects of intravenously infused acyclovir and other medications, even a long time after infusion, and the possible lack of initial local symptoms and signs. CONCLUSION: Early recognition of extravasation and prompt management are critical in preventing further morbidity, and optimizing outcomes.

Peripheral arteriovenous fistula as vascular access for long-term chemotherapy.

INTRODUCTION: To provide long-term vascular access in clinical oncology peripheral forearm veins (up to 95% of patients in Ukraine), central venous access and "complete implanted vascular systems" are used most often. Many oncology patients have contraindications to catheterization of superior vena cava. Besides, exploitation of central veins is associated with potential technical and infectious complications. The aim - to study short-term and long-term results of arteriovenous fistula exploitation as vascular access for continuous anticancer therapy. MATERIALS AND METHODS: Peripheral venous bed status in 41 oncology patients taking long-term chemotherapy treatment is analyzed in the article. Doppler sonography, morphologic and immune histochemical analyses were used in the study. RESULTS: Doppler sonography found qualitative and quantitative changes in forearm veins at different time periods after initiation of chemotherapy in the majority of patients. The major morphologic manifestations of venous wall damage were chemical phlebitis, local or extended hardening of venous wall, venous thrombosis and extravasations with necrosis and subsequent paravasal tissue sclerosis. Alternative vascular access created in 12 patients completely met the adequacy criteria (safety, multiple use, longevity, realization of the designed therapy program). The conclusion was made about inapplicability of forearm veins for long-term administration of cytostatic agents. If it is impossible to use central veins, arteriovenous fistula can become an alternative vascular access.

Negative-pressure wound therapy and early pedicle flap reconstruction of the chest wall after epirubicin extravasation.

PURPOSE: Accidental extravasation is a serious iatrogenic injury among patients receiving anthracycline-containing chemotherapy. The aim of this work is to present a combination therapy for chest wall reconstruction following epirubicin extravasation. METHODS: Herein, we report a 68-year-old woman with massive soft tissue necrosis of the anterolateral chest wall after epirubicin extravasation from a port implanted in the subclavicular area. RESULTS: The necrotic tissue was resected, the port was removed, and negative-pressure wound therapy was applied. Three weeks later, a latissimus dorsi pedicle flap was successfully used to cover the defect. CONCLUSIONS: To the best of the authors' knowledge, this is the first report of a strategy comprising the combination of negative-pressure wound therapy and a latissimus pedicle flap for reconstruction of the chest wall after soft tissue necrosis following epirubicin extravasation.

Angiopellosis as an Alternative Mechanism of Cell Extravasation.

Stem cells possess the ability to home in and travel to damaged tissue when injected intravenously. For the cells to exert their therapeutic effect, they must cross the blood vessel wall and enter the surrounding tissues. The mechanism of extravasation injected stem cells employ for exit has yet to be characterized. Using intravital microscopy and a transgenic zebrafish line Tg(fli1a:egpf) with GFP-expressing vasculature, we documented the detailed extravasation processes in vivo for injected stem cells in comparison to white blood cells (WBCs). While WBCs left the blood vessels by the standard diapedesis process, injected cardiac and mesenchymal stem cells underwent a distinct method of extravasation that was markedly different from diapedesis. Here, the vascular wall undergoes an extensive remodeling to allow the cell to exit the lumen, while the injected cell remains distinctively passive in activity. We termed this process Angio-pello-sis, which represents an alternative mechanism of cell extravasation to the prevailing theory of diapedesis. Stem Cells 2017;35:170-180 Video Highlight: https://youtu.be/i5EI-ZvhBps.

Hemoglobin extravasation in the brain of rats exchange-transfused with hemoglobin-based oxygen carriers.

Haemoglobin (Hb)-based oxygen carriers are under consideration as oxygen therapeutics. Their effect on apoptosis is critical, because the onset of pro-apoptotic pathways may lead to tissue damage. MP4OX, a polyethylene glycol-conjugated human Hb preserves the baseline level of neuron apoptosis with respect to sham. Here we develop a method for measuring Hb extravasation in brain. We exchange transfused rats by haemorrhaging 50% of their blood with simultaneous, isovolemic replacement with Hextend (negative control), MP4OX, or αα-cross-linked Hb. Animals were sacrificed 2 h after transfusion, brain tissue was harvested and processed for double-staining immunofluorescence, whereby Hb ? chain and NeuN (a neuron protein) were stained and quantitated. Whereas Hextend did not induce Hb extravasation, in both MP4OX and ??Hb brains Hb molecules were detected outside neurons. The level of extravasated Hb chains was > 3-fold higher in Hb compared to MP4OX. Western blot analysis revealed that the expression levels of protein related to redox imbalance (e.g., Nrf2, iNOS and ERK phosphorylation) were higher in ααHb than MP4OX. In conclusions, higher Hb extravasation in ααHb than MP4OX induces redox imbalance, which causes higher anti-oxidant response. Whereas Nrf2 response may be considered protective, iNOS response appears damaging.

Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways.

Aquaporin-4 (AQP4) is the most abundant water channel in the brain, and its inhibition before inducing focal ischemia, using the AQP4 inhibitor TGN-020, has been showed to reduce oedema in imaging studies. Here, we aimed to evaluate, for the first time, the histopathological effects of a single dose of TGN-020 administered after the occlusion of the medial cerebral artery (MCAO). On a rat model of non-reperfusion ischemia, we have assessed vascular densities, albumin extravasation, gliosis, and apoptosis at 3 and 7 days after MCAO. TGN-020 significantly reduced oedema, glial scar, albumin effusion, and apoptosis, at both 3 and 7 days after MCAO. The area of GFAP-positive gliotic rim decreased, and 3D fractal analysis of astrocytic processes revealed a less complex architecture, possibly indicating water accumulating in the cytoplasm. Evaluation of the blood vessels revealed thicker basement membranes colocalizing with exudated albumin in the treated animals, suggesting that inhibition of AQP4 blocks fluid flow towards the parenchyma in the paravascular drainage pathways of the interstitial fluid. These findings suggest that a single dose of an AQP4 inhibitor can reduce brain oedema, even if administered after the onset of ischemia, and AQP4 agonists/antagonists might be effective modulators of the paravascular drainage flow.

Glycoengineering of E-Selectin Ligands by Intracellular versus Extracellular Fucosylation Differentially Affects Osteotropism of Human Mesenchymal Stem Cells.

Human mesenchymal stem cells (MSCs) hold great promise in cellular therapeutics for skeletal diseases but lack expression of E-selectin ligands that direct homing of blood-borne cells to bone marrow. Previously, we described a method to engineer E-selectin ligands on the MSC surface by exofucosylating cells with fucosyltransferase VI (FTVI) and its donor sugar, GDP-Fucose, enforcing transient surface expression of the potent E-selectin ligand HCELL with resultant enhanced osteotropism of intravenously administered cells. Here, we sought to determine whether E-selectin ligands created via FTVI-exofucosylation are distinct in identity and function to those created by FTVI expressed intracellularly. To this end, we introduced synthetic modified mRNA encoding FTVI (FUT6-modRNA) into human MSCs. FTVI-exofucosylation (i.e., extracellular fucosylation) and FUT6-modRNA transfection (i.e., intracellular fucosylation) produced similar peak increases in cell surface E-selectin ligand levels, and shear-based functional assays showed comparable increases in tethering/rolling on human endothelial cells expressing E-selectin. However, biochemical analyses revealed that intracellular fucosylation induced expression of both intracellular and cell surface E-selectin ligands and also induced a more sustained expression of E-selectin ligands compared to extracellular fucosylation. Notably, live imaging studies to assess homing of human MSC to mouse calvarium revealed more osteotropism following intravenous administration of intracellularly-fucosylated cells compared to extracellularly-fucosylated cells. This study represents the first direct analysis of E-selectin ligand expression programmed on human MSCs by FTVI-mediated intracellular versus extracellular fucosylation. The observed differential biologic effects of FTVI activity in these two contexts may yield new strategies for improving the efficacy of human MSCs in clinical applications. Stem Cells 2016;34:2501-2511.

Numerical simulation of a single cell passing through a narrow slit.

The narrow slit between endothelial cells that line the microvessel wall is the principal pathway for tumor cell extravasation to the surrounding tissue. To understand this crucial step for tumor hematogenous metastasis, we used dissipative particle dynamics method to investigate an individual cell passing through a narrow slit numerically. The cell membrane was simulated by a spring-based network model which can separate the internal cytoplasm and surrounding fluid. The effects of the cell elasticity, cell shape, nucleus and slit size on the cell transmigration through the slit were investigated. Under a fixed driving force, the cell with higher elasticity can be elongated more and pass faster through the slit. When the slit width decreases to 2/3 of the cell diameter, the spherical cell becomes jammed despite reducing its elasticity modulus by 10 times. However, transforming the cell from a spherical to ellipsoidal shape and increasing the cell surface area by merely 9.3 % can enable the cell to pass through the narrow slit. Therefore, the cell shape and surface area increase play a more important role than the cell elasticity in cell passing through the narrow slit. In addition, the simulation results indicate that the cell migration velocity decreases during entrance but increases during exit of the slit, which is qualitatively in agreement with the experimental observation.

Extravasation injuries.

It is common for an intravascular catheter to be inserted to administer various types of therapy. Extravasation occurs frequently, and in the most severe cases plastic surgeons are often summoned to assess the extent of the injury and the possibility for reconstruction. The Department of Plastic and Reconstructive Surgery at Oslo University Hospital assesses approximately 15 severe cases of this type each year.