Lennart Wiman (photographer) is acknowledged for excellent video recording.

Patienten mit schriftlicher Einverständniserklärung und die Studie wurde von der Regional Ethical Review Board an der Universität Göteborg genehmigt. 1. Anästhesie <ol><li> Richten Sie alle Überwachung (EKG, Blutdruckmanschette) 17. </li><li> Legen Sie eine Epiduralkatheter im unteren bis mittleren thorakalen Ebene 17. </li><li> Induzieren Narkose mit Propofol 2 mg / kg, 150 &amp; mgr; g Fentanyl und Rocuronium 0,6 mg / kg durch einen zuvor einge peripheren Venenkatheter. </li><li> Preoxygenate und Intubation des Patienten. Aufrechterhaltung einer Narkose mit Sevofluran, Sauerstoff und Luft 17. </li><li> Legen Sie eine Doppellumen-ZVK und einen arteriellen Katheter. Überwachen CVP und arteriellen Druck 17. </li></ol> 2. Isolierung der Leber und Kanülierung der Gefäße <ol><li> Verwalten 100 IE / kg Heparin und geben Antibiotikaprophylaxe (zB 160 mg Trimethoprim und 800 mg Sulfamethoxazol). </li><li> Mit der perkutanen Seldinger-Technik, setzen Sie ein 17 Fr Katheter in die Vena femoralis und eine 15 Fr Katheter in der V. jugularis externa 18. Überprüfen Sie die Positionen der Katheter durch Fluoroskopie. </li><li> Durchführen einer Laparotomie durch einen L-förmigen Einschnitt von der Schwertfortsatz entlang der Mittellinie und dann auf eine richtige subcostal Einschnitt 19 erstreckt. </li><li> Stellen Sie sicher, dass keine außerLeberMetastasen vorhanden sind in den Unterleib mit einer kompletten Inspektion und Palpation. <ol><li> Wenn irgendwelche verdächtigen Läsionen gefunden werden, überprüfen Malignität durch Gefrierschnitt. </li><li> Beenden Sie das Verfahren, wenn es Anzeichen für extrahepatische Manifestation (periaortal Adenopathie, Bauch Metastasen). Lymphadenopathie in der Leberpforte wird nicht als Kontraindikation. </li></ol></li><li> Mobilisieren der Leber durch Dividieren des Ligamentum falciforme, die linken und rechten Dreiecksbandes und die koronare Ligament 19. </li><li> Präparieren Sie die Kava-Venen beginnend von den Nierenvenen bis zu der Membran mit Unterbindung der retroperitonealen Nebenvenen. </li><li> Identifizieren Sie die rechte Neben Vene und setzen Sie ein Gefäß Schleife um ihn herum. </li><li> Identifizieren Sie den rechten Gonaden Vene. Sezieren für 5-10 cm. Legen Sie eine Tabaksbeutelnaht um den Eingang zur Hohlvene. <ol><li> Legen Sie eine Ligatur distal an der Gonaden Vene. Mit einer Schere, öffnen Sie die Gonaden Vene 3-5 cm von der Hohlvene. </li><li> Legen Sie eine 18 Fr drahtverstärkte Katheter durch die rechte Gonaden Vene und legen Sie die Spitze retrohepatically über den Nierenvenen. </li><li> Legen Sie eine Ligatur um die Gonaden Vene, um die Position des Katheters zu sichern. </li><li> Überprüfen Sie den Rückfluss des Blutes durch den Katheter. Heparinisierung des Katheters 18. </li></ol></li><li> Präparieren Sie die Ligamentum hepatoduodenale und visualisieren die gemeinsame Leberarterie, der gastroduodenalen Arterie und die richtige Leberarterie. <ol><li> Platz Vesselloops um die gemeinsame Leber artery und die gastrodoudenal Arterie. </li><li> Präparieren Sie die Pfortader und setzen Sie ein Gefäß Schleife um ihn herum. </li><li> Isolieren der Rest des Bandes, die den Gallengang und umfassen all dies in einem Gefäß Schleife. </li></ol></li><li> Heben Sie den gastroduodenalen Arterie mit der Gefäßschleife. Nach Unterbrechung des arteriellen Zustroms, einen Einschnitt mit einer Schere. <ol><li> Legen Sie eine 8-12 Fr Katheter mit seiner Spitze in die richtige Leberarterie. Sichern Sie die Position mit einer Ligatur um den gastroduodenalen Arterie. </li><li> Stellen Sie sicher, Blutrück im Katheter und dann Heparinisierung es 18. </li></ol></li><li> Prime das Perfusionssystem mit einer Einheit verpackt Erythrozyten, 100 ml Albumin (50 g / l), 100 ml Tribonat (Natriumbicarbonat), 2500 Einheiten Heparin (5000 IE / ml) und 250 ml Kristalloide. </li><li> Verbinden des arteriellen und die Hohlvene Katheter zur Perfusion System bestehend aus einem Herz-Lungen-Maschine mit einer Walzenpumpe ausgestattet und einen Heizer temeinsam mit venösen Reservoir, Oxygenator und Schlauchsysteme von Einweg-Typ. </li><li> Verbinden die femoralen und externen jugularen Katheter zur venovenöse Bypasspumpe, bestehend aus einer Zentrifugalpumpe, zusammen mit einer Heizeinheit und starten Bypass. </li><li> Schließen Sie die Isolierung der Leber durch Anziehen einer Rumel Stauschlauch an der Hohlvene infrahepatically über den Nierenvenen und Einspannen der Hohlvene suprahepatically mit einem Klintmalm Gefäßklemme. <ol><li> Ziehen Sie eine Rumel Stauschlauch an den gemeinsamen Gallengang, der Pfortader und der rechten Neben Vene und schließlich klemmen die Leberarterie mit einer Gefäßklemme. </li></ol></li></ol> 3. Die Perfusion <ol><li> Starten Sie die Durchblutung und den Blutspiegel im venösen Reservoir manuell überwachen. Die Durchflussmenge, bis ein konstantes Niveau erreicht ist, in der Regel eine Durchflussrate zwischen 500-1,200 ml / min. </li><li> Zeigen Thermistorsonden in die rechten und linken Leberlappen und einem direkt inder arterielle Katheter. </li><li> Erhitzen Sie das Perfusat, die auf eine Leberzieltemperatur von 40 o C. Halten Sie diese Temperatur während des Durchblutung. </li><li> Legen Sie eine Szintillationssonde über die venovenöse Bypasspumpe Kopf. </li><li> Kalibrieren des Leckageüberwachungssystems, durch Einspritzen einer kleinen Dosis von 10 MBq 99m Tc-Albumin (1 ml) in den systemischen Kreislauf und Registrieren der Grundlinienaktivität. <ol><li> Einprägen des zehnfach höheren Dosis, 100 MBq 99m Tc-Albumin (1 ml), in die Leberperfusion Einheit. </li><li> Nehmen ein Austreten aus dem Perfusionssystem in die systemische Zirkulation als Zunahme der Aktivität durch das Szintillations-Sonde gemessen. </li><li> Nehmen jegliche Leckage aus der systemischen Zirkulation zum Perfusionssystem als eine Volumenzunahme im venösen Reservoir. </li></ol></li><li> Beim stationären Zustand des Durchflusses eingerichtet ist, keine Leckage vorhanden ist und die Lebertemperatur 40 ° C erreicht hat, einzuspritzen Melphalan in einer Dosis von1 mg / kg Körpergewicht in das Perfusionssystem in zwei Dosen verabreicht 30 Minuten auseinander dividiert. </li></ol> 4. Beenden Sie die Perfusion und Katheter entfernen <ol><li> Nach 60 min der Perfusion, leeren Sie den Perfusat aus dem System und bewässern die Leber mit 1000 ml Kristalloide. </li><li> Fügen Sie eine Einheit von gepackten Erythrozyten an die Perfusion Einheit, ziehen lassen in die Leber und dann stoppen Sie die Durchblutung. </li><li> Lassen Sie die Klintmalm Klemme und die Rumel Aderpresse aus der Hohlvene. </li><li> Lassen Sie die Rumel Aderpresse aus dem Ligamentum hepatoduodenale. </li><li> Nehmen Sie die Unterbindung von der gastroduodenalen Arterie. Entfernen Sie den Katheter und Ligation des Gefäßes. </li><li> Lösen Sie die Klemme aus der Leberarterie. </li><li> Entfernen des Katheters aus gonadalen Vene und Ligieren des Gefäßes. </li><li> Stoppen Sie den venovenöse Bypasspumpe und ziehen Sie die Rohre. </li><li> Schließen Sie den Bauch mit einer ununterbrochenen Naht Faszien und dann eine intrakutane Hautnaht. </li><li> Entfernen Sie die catheters in den Oberschenkel und externen Jugularvenen und gelten lokalen Druck 5 Min. </li></ol> 5. Postoperative Behandlung <ol><li> Extubieren den Patienten und Transfer zum postoperativen Intensivstation für 24 Stunden. Halten Überwachung der zentrale Venendruck und arterielle Blutdruck. </li><li> Bringen Sie den Patienten an einen chirurgischen Abteilung für ein typisches von 3-7 Tagen nach der post-operative Betreuung. </li><li> Weiter mit Heparin mit niedrigem Molekular (LMWH) in einer Dosis von 5000 IE / Tag für insgesamt 4 Wochen. </li></ol>

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The authors have nothing to disclose.

Patienten mit metastasiertem Aderhautmelanom haben nur wenige Behandlungsmöglichkeiten. Chemotherapie 6, Immuntherapie 23 und zielgerichtete Therapie 24 nicht in der Lage, um eine verbesserte OS zeigen. Bei Patienten mit Lebermetastasen wenigen ist Leberresektion eine Option 12. Andere Behandlungen umfassen Leberintraarterieller Chemotherapie (HIA) 9, transarteriellen Chemoembolisation (TACE) 25 und selektive interne Radiotherapie (SIRT) 26. <...

Aderhautmelanom ist der häufigste primäre intraokulare Malignität in Erwachsene, die Inzidenz am höchsten in der kaukasischen Bevölkerung ein. Lokale Behandlung besteht in der Enukleation oder lokalen Plaque Strahlentherapie 2,3. Unabhängig von lokalen Behandlung wird Metastasen entwickeln schließlich in etwa 35-50% der Patienten 4,5. Die Leber ist die häufigste Stelle der Metastasen und etwa 50% der mit isolierten Lebermetastasen Patienten. Das mediane Gesamtüberleben (OS) für Patienten mit Lebermetastasen ist 6-12 Monate 4. Mehrere verschiedene systemische und regionale Behandlungsstrategien untersucht worden, aber die Überlebensraten haben sich nicht verbessert 2. Die Behandlung mit systemischen Chemotherapie, die beide Einzelsubstanz (Dacarbazin oder Temozolomid 6) oder Kombinationsbehandlungen (BOLD-Schema 7, Gemcitabin mit Treosulfan 8), zeigt Ansprechraten von weniger als10%. Leberintraarteriellen Chemotherapie (HIA) hat einen etwas höheren Gesamtreaktionsrate im Vergleich zur systemischen Chemotherapie, aber keine Erhöhung der Gesamtüberlebens 9 gezeigt. Transarteriellen Chemoembolisation (TACE) mit Cisplatin und Carboplatin zeigten eine partielle Remission in 57% der Patienten mit einer medianen Überlebens von 9 Monaten 10. Selektive interne Radiotherapie (SIRT) wurde eine partielle Remission in 62% der Patienten mit einer medianen Überlebens von 7 Monaten 11 gezeigt. In einer Studie zur Leberresektion, darunter 255 Patienten wurde ein Gesamtüberleben von 14 Monaten ausgewiesen; in 76 der Patienten, bei denen eine mikroskopisch vollständige Resektion möglich war, war die Überlebensrate 27 Monate 12. Isolierte Leberperfusion (IHP) ist eine regionale Behandlungsoption, die ursprünglich von Ryan und Ausman entwickelt. Die Logik hinter der Technik ist es, operativ zu isolieren und Perfusion der Leber mit einer hohen Dosis eines chemotherapeutischen Mittels unter Vermeidung systemischxicity 13. Darüber hinaus vermittelt die gleichzeitige Hyperthermie eine erhöhte Aufnahme des chemotherapeutischen Mittels durch Änderungen in der Tumordurchblutung und zellulärer Membranpermeabilität 14. Vollständige Gefäß Isolierung mit einem radioaktiven Tracer-Technik unter Verwendung von Tc-99 markierten menschlichen Serumalbumin 15 bestätigt. In einer retrospektiven Studie der Phase II hat eine mögliche Überlebensvorteil von 14 Monaten (26 vs. 12 Monate) bei Patienten, die IHP erlebte im Vergleich zu den längsten Überlebenden mit Aderhautmelanom Lebermetastasen in Schweden 16 gezeigt. Hier stellen wir die Technik des IHP mit einem kurzen Überblick über die aktuellen Ergebnisse und Zukunftsperspektiven.

<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td>Wire re-inforced catethers</td>
			<td>Medtronic Inc, Minnesota, USA</td>
			<td></td>
			<td>12-18Fr</td>
		</tr>
		<tr>
			<td>St&#246;ckert S5</td>
			<td>Sorin Group, Mirandola, Italy</td>
			<td></td>
			<td>Heart-lung machine</td>
		</tr>
		<tr>
			<td>Rotaflow</td>
			<td>Maquet, Jostra Medizintechnik AG, Hirrlingen, Germany</td>
			<td></td>
			<td>Centrifugal pump</td>
		</tr>
		<tr>
			<td>HU 35</td>
			<td>Maquet cardiopulmonary AG, Hirrlingen, Germany</td>
			<td></td>
			<td>Heater unit</td>
		</tr>
		<tr>
			<td>Flexbumin 200 g/l</td>
			<td>Baxter Medical AB, Kista, Sweden</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Tribonat</td>
			<td>Fresenius Kabi AB, Uppsala, Sweden</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Heparin LEO, 5000 IE/ml</td>
			<td>LEO Pharma AB, Sweden</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Ringer Acetate</td>
			<td>Baxter Medical AB, Kista, Sweden</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Vasculosis</td>
			<td>Cis-Bio International, Gif-Sur-Yvette, France</td>
			<td></td>
			<td>99mTc-albumin</td>
		</tr>
		<tr>
			<td>MedicView</td>
			<td>SystemData AB, Gothenburg, Sweden</td>
			<td></td>
			<td>Leakage monitoring system</td>
		</tr>
		<tr>
			<td>Alkeran</td>
			<td>Aspen Europe GmbH, Bad Oldesloe, Germany</td>
			<td></td>
			<td>melphalan</td>
		</tr>
	</tbody>
</table>

isolated hepatic perfusion as a treatment for liver metastases of uveal melanoma

Isolierte Leberperfusion (IHP) ist ein Verfahren, bei dem die Leber wird chirurgisch isoliert und mit einer hohen Konzentration des Chemotherapeutikums Melphalan perfundiert. Kurz gesagt, beginnt das Verfahren mit dem Aufbau einer perkutanen veno-venöse Bypass aus der Oberschenkelvene an die externe Halsschlagader. Über eine Laparotomie werden Katheter dann in die richtige Leberarterie und der Hohlvene eingesetzt. Die Pfortader und Hohlvene, sowohl supra- und infrahepatically, werden dann eingespannt. Die arterielle und venöse Katheter an eine Herz-Lungen-Maschine verbunden ist, und die Leber mit Melphalan (1 mg / kg Körpergewicht) für 60 min perfundiert. Auf diese Weise ist es möglich, lokal Perfusion der Leber mit einer hohen Dosis eines chemotherapeutischen Mittels, ohne Leckage in die systemische Zirkulation. In früheren Studien mit Patienten mit isolierter Lebermetastasen von Aderhautmelanom, eine allgemeine Ansprechrate von 33 bis 100% und eine mediane Überlebenszeit von 9 bis 13 Monate,berichtet worden. Ziel dieses Protokolls ist es, eine klare Beschreibung, wie man das Verfahren durchführen zu geben und IHP als Behandlungsoption für Lebermetastasen von Aderhautmelanom diskutieren.

Ein erster Bericht enthalten 22 Patienten mit Melphalan mit oder ohne TNF-alpha behandelt. Die Ergebnisse zeigten eine Gesamtansprechrate von 62%, davon zwei Patienten mit CR (10%) und eine mediane Überlebenszeit von 11 Monaten 20. Eine weitere Studie berichtet über die Ergebnisse der 29 aufeinander folgenden Patienten behandelt mit Melphalan allein. Das Ergebnis war sehr ähnlich mit 62% Gesamtansprechrate einschließlich 10% komplette Remission und eine mediane Überlebenszeit von 12 Monaten 21.</sup...

Watch this Scientific Journal Video about Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma at JoVE.com

Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma

Here, we present a protocol how to perform an isolated liver perfusion (IHP) with melphalan and we also discuss IHP as a treatment option for liver metastases of uveal melanoma.

Isolierte Leberperfusion als Behandlung für Lebermetastasen von Aderhautmelanom

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic ...

isolated-hepatic-perfusion-as-treatment-for-liver-metastases-uveal

Research

JoVE Journal

Medicine

13.3K Aufrufe.  Institute of Clinical Sciences. Here, we present a protocol how to perform an isolated liver perfusion (IHP) with melphalan and we also discuss IHP as a treatment option for liver metastases of uveal melanoma.

Serie: Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma

Surgical Procedures for a Rat Model of Partial Orthotopic Liver Transplantation with Hepatic Arterial Reconstruction

Orthotopic liver transplantation (OLT) in rats using a whole or partial graft is an indispensable experimental model for transplantation research, such as studies on graft preservation and ischemia-reperfusion injury 1,2, immunological responses 3,4, hemodynamics 5,6, and small-for-size syndrome 7. The rat OLT is among the most difficult animal models in experimental surgery and demands advanced microsurgical skills that take a long time to learn. Consequently, the use of this model has been limited. Since the reliability and reproducibility of results are key components of the experiments in which such complex animal models are used, it is essential for surgeons who are involved in rat OLT to be trained in well-standardized and sophisticated procedures for this model.
While various techniques and modifications of OLT in rats have been reported 8 since the first model was described by Lee et al. 9 in 1973, the elimination of the hepatic arterial reconstruction 10 and the introduction of the cuff anastomosis technique by Kamada et al. 11 were a major advancement in this model, because they simplified the reconstruction procedures to a great degree. In the model by Kamada et al., the hepatic rearterialization was also eliminated. Since rats could survive without hepatic arterial flow after liver transplantation, there was considerable controversy over the value of hepatic arterialization. However, the physiological superiority of the arterialized model has been increasingly acknowledged, especially in terms of preserving the bile duct system 8,12 and the liver integrity 8,13,14.
In this article, we present detailed surgical procedures for a rat model of OLT with hepatic arterial reconstruction using a 50% partial graft after ex vivo liver resection. The reconstruction procedures for each vessel and the bile duct are performed by the following methods: a 7-0 polypropylene continuous suture for the supra- and infrahepatic vena cava; a cuff technique for the portal vein; and a stent technique for the hepatic artery and the bile duct.

Orthotopic liver transplantation in rats is an indispensable experimental model for biomedical research. Here we present our surgical procedures for orthotopic rat liver transplantation with hepatic arterial reconstruction using a 50% partial graft.

Chirurgische Verfahren für eine Ratte Modell Teilweise Lebertransplantation mit arteriellen Rekonstruktion

Orthotopic liver transplantation (OLT) in rats using a whole or partial graft is an indispensable experimental model for transplantation research, such as ...

Forschung

Medizin

A Preclinical Murine Model of Hepatic Metastases

Numerous murine models have been developed to study human cancers and advance the understanding of cancer treatment and development. Here, a preclinical, murine pancreatic tumor model of hepatic metastases via a hemispleen injection of syngeneic murine pancreatic tumor cells is described. This model mimics many of the clinical conditions in patients with metastatic disease to the liver. Mice consistently develop metastases in the liver allowing for investigation of the metastatic process, experimental therapy testing, and tumor immunology research.

A preclinical, murine model of hepatic metastases performed via a hemispleen injection technique.

Einer präklinischen Mausmodell der Lebermetastasen

Numerous murine models have been developed to study human cancers and advance the understanding of cancer treatment and development. Here, a preclinical, ...

MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD17) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.

Here we outline the procedure for MRI-guided repetitive transcranial magnetic stimulation to the dorsomedial prefrontal cortex as an experimental treatment for major depressive disorder.

MRI-geführte dmPFC-rTMS zur Behandlung behandlungsresistente Major Depressive Disorder

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial ...

Percutaneous Hepatic Perfusion (PHP) with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn unresectable metastases into resectable ones. Some patients however, suffer from side effects or progression under systemic treatment. For patients with metastasized uveal melanoma there are no standard systemic therapy options. For patients without extrahepatic disease, isolated liver perfusion (IHP) may enable local disease control with limited systemic side effects. Previously, this was performed during open surgery with satisfying results, but morbidity and mortality related to the open procedure, prohibited a widespread application. Therefore, percutaneous hepatic perfusion (PHP) with simultaneous chemofiltration was developed. Besides decreasing morbidity and mortality, this procedure can be repeated, hopefully leading to a higher response rate and improved survival (by local control of disease). During PHP, catheters are placed in the proper hepatic artery, to infuse the chemotherapeutic agent, and in the inferior caval vein to aspirate the chemosaturated blood returning through the hepatic veins. The caval vein catheter is a double balloon catheter that prohibits leakage into the systemic circulation. The blood returning from the hepatic veins is aspirated through the catheter fenestrations and then perfused through an extra-corporeal filtration system. After filtration, the blood is returned to the patient by a third catheter in the right internal jugular vein. During PHP a high dose of melphalan is infused into the liver, which is toxic and would lead to life threatening complications when administered systemically. Because of the significant hemodynamic instability resulting from the combination of caval vein occlusion and chemofiltration, hemodynamic monitoring and hemodynamic support is of paramount importance during this complex procedure.

Percutaneous Hepatic Perfusion PHP with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver

In this manuscript, we describe percutaneous isolated hepatic perfusion with simultaneous chemofiltration as treatment for unresectable liver metastases. This procedure is performed under general anaesthesia in the angiosuite by an experienced team, consisting of an interventional radiologist, a clinical perfusionist and anaesthesiologist.

Die perkutane Leberperfusion (PHP) mit Melphalan als Behandlung für inoperablen Metastasen auf die Leber beschränkt

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn ...

Generation of a Humanized Mouse Liver Using Human Hepatic Stem Cells

A novel animal model involving chimeric mice with humanized livers established via human hepatocyte transplantation has been developed. These mice, in which the liver has been repopulated with functional human hepatocytes, could serve as a useful tool for investigating human hepatic cell biology, drug metabolism, and other preclinical applications. One of the key factors required for successful transplantation of human hepatocytes into mice is the elimination of the endogenous hepatocytes to prevent competition with the human cells and provide a suitable space and microenvironment for promoting human donor cell expansion and differentiation. To date, two major liver injury mouse models utilizing fumarylacetoacetate hydrolase (Fah) and uroplasminogen activator (uPA) mice have been established. However, Fah mice are used mainly with mature hepatocytes and the application of the uPA model is limited by decreased breeding. To overcome these limitations, Alb-toxin receptor mediated cell knockout (TRECK)/SCID mice were used for in vivo differentiation of immature human hepatocytes and humanized liver generation. Human hepatic stem cells (HpSCs) successfully repopulated the livers of Alb-TRECK/SCID mice that had developed lethal fulminant hepatic failure following diphtheria toxin (DT) treatment. This model of a humanized liver in Alb-TRECK/SCID mice will have functional applications in studies involving drug metabolism and drug-drug interactions and will promote other in vivo and in vitro studies.

Here, we present a novel humanized mouse liver model generated in Alb-toxin receptor mediated cell knockout (TRECK)/SCID mice following the transplantation of immature and expandable human hepatic stem cells.

Erzeugung eines humanisierten Maus-Leber unter Einsatz von menschlichem Leberstammzellen

A novel animal model involving chimeric mice with humanized livers established via human hepatocyte transplantation has been developed. These mice, in ...

Method of Direct Segmental Intra-hepatic Delivery Using a Rat Liver Hilar Clamp Model

Major hepatic surgery with inflow occlusion, and liver transplantation, necessitate a period of warm ischemia, and a period of reperfusion leading to ischemia/reperfusion (I/R) injury with myriad negative consequences. Potential I/R injury in marginal organs destined for liver transplantation contributes to the current donor shortage secondary to a decreased organ utilization rate. A significant need exists to explore hepatic I/R injury in order to mediate its impact on graft function in transplantation. Rat liver hilar clamp models are used to investigate the impact of different molecules on hepatic I/R injury. Depending on the model, these molecules have been delivered using inhalation, epidural infusion, intraperitoneal injection, intravenous administration or injection into the peripheral superior mesenteric vein. A rat liver hilar clamp model has been developed for use in studying the impact of pharmacologic molecules in ameliorating I/R injury. The described model for rat liver hilar clamp includes direct cannulation of the portal supply to the ischemic hepatic segment via a side branch of the portal vein, allowing for direct segmental hepatic delivery. Our approach is to induce ischemia in the left lateral and median lobes for 60 min, during which time the substance under study is infused. In this case, pegylated-superoxide dismutase (PEG-SOD), a free radical scavenger, is infused directly into the ischemic segment. This series of experiments demonstrates that infusion of PEG-SOD is protective against hepatic I/R injury. Advantages of this approach include direct injection of the molecule into the ischemic segment with consequent decrease in volume of distribution and reduction in systemic side effects.

A unique rat liver hilar clamp model was developed for studying the impact of pharmacologic molecules in ameliorating ischemia-reperfusion injury. This model includes direct cannulation of the portal supply to the ischemic liver segment via a branch of the portal vein, allowing for direct hepatic delivery.

Methode der direkten segmentale Intra-Leber-Lieferung Mit einer Rattenleber Hilar Clamp Modell

Major hepatic surgery with inflow occlusion, and liver transplantation, necessitate a period of warm ischemia, and a period of reperfusion leading to ...

Treatment of Liver Metastases Using an Internal Target Volume Method for Stereotactic Body Radiotherapy

The prognosis of patients with metastatic cancers has improved in the past decades due to effective chemotherapy and oligometastatic surgery. For inoperable patients, local ablation therapies, such as stereotactic body radiotherapy (SBRT), can provide effective local tumor control with minimal toxicity. Because of its high precision and accuracy, SBRT delivers a higher radiation dose per fraction, is more effective, and targets smaller irradiation volumes than does conventional radiotherapy. In addition, steep dose gradients from target lesions to surrounding normal tissues are achieved using SBRT; thus, SBRT provides more effective tumor control and exhibits fewer side effects than conventional radiotherapy. The use of SBRT is prevalent for treating intracranial lesions (known as stereotactic radiosurgery); however, it is now also used for treating spinal and adrenal metastases. Because of advancements in image-guided assistance and respiratory motion management, several studies have investigated the use of SBRT for treating lung or liver tumors, which move as a patient breathes. The results of these studies have suggested that SBRT favorably controls tumors in the case of moving lesions.
Four-dimensional computed tomography (4D-CT) with an abdominal compressor (AC) is clinically convenient for effective respiratory motion management. Because this method is noninvasive and allows free breathing, its use reduces complications. Furthermore, patients consider this method convenient. Moreover, it is considered more efficient than other methods of respiratory motion management by physicians and therapists. The use of 4D-CT with an AC for treating pulmonary lesions has also been widely investigated, and the technique is gaining acceptance for treating hepatic lesions. However, the protocols for using 4D-CT with an AC for treating hepatic lesions are different from those used for treating pulmonary lesions. In this article, we describe a new protocol for SBRT with 4D-CT and an AC for treating liver metastases.

Stereotactic body radiotherapy (SBRT) requires rigorous accuracy and precision for delivering high radiation doses per fraction to small treatment volumes to improve tumor control and simultaneously reduce toxicity. Herein, we present a noninvasive and clinically convenient respiratory motion management protocol for SBRT for liver metastases.

Behandlung von Lebermetastasen mit ein internes Ziel-Volumen-Methode für Stereotaktische Körper Strahlentherapie

The prognosis of patients with metastatic cancers has improved in the past decades due to effective chemotherapy and oligometastatic surgery. For ...

A Small Animal Model of Ex Vivo Normothermic Liver Perfusion

There is a significant shortage of liver allografts available for transplantation, and in response the donor criteria have been expanded. As a result, normothermic ex vivo liver perfusion (NEVLP) has been introduced as a method to evaluate and modify organ function. NEVLP has many advantages in comparison to hypothermic and subnormothermic perfusion including reduced preservation injury, restoration of normal organ function under physiologic conditions, assessment of organ performance, and as a platform for organ repair, remodeling, and modification. Both murine and porcine NEVLP models have been described. We demonstrate a rat model of NEVLP and use this model to show one of its important applications &#8212; the use of a therapeutic molecule added to liver perfusate. Catalase is an endogenous reactive oxygen species (ROS) scavenger and has been demonstrated to decrease ischemia-reperfusion in the eye, brain, and lung. Pegylation has been shown to target catalase to the endothelium. Here, we added pegylated-catalase (PEG-CAT) to the base perfusate and demonstrated its ability to mitigate liver preservation injury. An advantage of our rodent NEVLP model is that it is inexpensive in comparison to larger animal models. A limitation of this study is that it does not currently include post-perfusion liver transplantation. Therefore, prediction of the function of the organ post-transplantation cannot be made with certainty. However, the rat liver transplant model is well established and certainly could be used in conjunction with this model. In conclusion, we have demonstrated an inexpensive, simple, easily replicable NEVLP model using rats. Applications of this model can include testing novel perfusates and perfusate additives, testing software designed for organ evaluation, and experiments designed to repair organs.

A Small Animal Model of Ex Vivo Normothermic Liver Perfusion

There is a significant liver donor shortage, and criteria for liver donors have been expanded. Normothermic ex vivo liver perfusion (NEVLP) has been developed to evaluate and modify organ function. This study demonstrates a rat model of NEVLP and tests the ability of pegylated-catalase, to mitigate liver preservation injury.

Ein kleines Tier Modell der Ex Vivo Normothermic Leber Perfusion

There is a significant shortage of liver allografts available for transplantation, and in response the donor criteria have been expanded. As a result, ...

Measurement of the Hepatic Venous Pressure Gradient and Transjugular Liver Biopsy

Here we provide a detailed protocol describing the clinical procedure of hepatic venous pressure gradient (HVPG) measurement in patients with advanced chronic liver disease followed by an instruction for transjugular biopsy. Under local anesthesia and ultrasound guidance, a catheter introducer sheath is placed in the right internal jugular vein. Using&#160;fluoroscopic guidance, a balloon catheter is advanced into the inferior vena cava (IVC) and inserted into a large hepatic vein. Correct and sufficient wedge position of the catheter is ensured by injecting contrast media while the balloon is blocking the outflow of the cannulated hepatic vein. After calibrating the external pressure transducer, continuous pressure recordings are obtained with triplicate recordings of the wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP). The difference between FHVP and WHVP is referred to as HVPG, with values &#8805;10 mm Hg indicating clinically significant portal hypertension (CSPH). Before removing the catheter, pressure readings obtained in the IVC at the same level, as well as the right atrial pressure are recorded.
Finally, a transjugular liver biopsy can be obtained via the same vascular route. Different systems are available; however, core biopsy needles are preferred over aspiration needles, especially for cirrhotic livers. Again, under fluoroscopic guidance a biopsy needle introducer sheath is advanced into an hepatic vein. Next, the transjugular biopsy needle is gently advanced through the introducer sheath: (i) in case of aspiration biopsy, the needle is advanced into the liver parenchyma under aspiration and then removed quickly, or (ii) in case of a core biopsy, the cutting-mechanism is triggered inside the parenchyma. Several separate passages can be safely performed to obtain sufficient liver specimens via transjugular biopsy. In experienced hands, the combination of these procedures takes about 30-45 min.

Here, we present a protocol for measurement of hepatic venous pressure gradient (HVPG),the gold standard to diagnose clinically significant portal hypertension. Moreover, we describe how to perform a transjugular liver biopsy within the same session.

Messung des Lebervenendruckgradienten und der transjugularen Leberbiopsie

Here we provide a detailed protocol describing the clinical procedure of hepatic venous pressure gradient (HVPG) measurement in patients with advanced ...

Murine Precision-Cut Liver Slices as an Ex Vivo Model of Liver Biology

Understanding the mechanisms of liver injury, hepatic fibrosis, and cirrhosis that underlie chronic liver diseases (i.e., viral hepatitis, non-alcoholic fatty liver disease, metabolic liver disease, and liver cancer) requires experimental manipulation of animal models and in vitro cell cultures. Both techniques have limitations, such as the requirement of large numbers of animals for in vivo manipulation. However, in vitro cell cultures do not reproduce the structure and function of the multicellular hepatic environment. The use of precision-cut liver slices is a technique in which uniform slices of viable mouse liver are maintained in laboratory tissue culture for experimental manipulation. This technique occupies an experimental niche that exists between animal studies and in vitro cell culture methods. The presented protocol describes a straightforward and reliable method to isolate and culture precision-cut liver slices from mice. As an application of this technique, ex vivo liver slices are treated with bile acids to simulate cholestatic liver injury and ultimately assess the mechanisms of hepatic fibrogenesis.

This protocol provides a simple and reliable method for the production of viable precision-cut liver slices from mice. The ex vivo tissue samples can be maintained under laboratory tissue culture conditions for multiple days, providing a flexible model to examine liver pathobiology.

Murine Präzisionsgeschnittene Leberscheiben als Ex-Vivo-Modell der Leberbiologie

Understanding the mechanisms of liver injury, hepatic fibrosis, and cirrhosis that underlie chronic liver diseases (i.e., viral hepatitis, non-alcoholic ...