Name: isolated hepatic perfusion as a treatment for liver metastases of uveal melanoma
Uploaded: 2015-01-25T14:00:00.000+00:00
Duration: 9 min 52 s
Description: Watch this Scientific Journal Video about Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma at JoVE.com

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

환자 동의서를 작성 제공하고, 연구는 예테보리 대학에서 지역 윤리 심의위원회에 의해 승인되었다. 1. 마취 <ol><li> 모든 모니터링 (ECG, 혈압 커프) (17)을 설정합니다. </li><li> 중반 흉부 레벨 17 아래에서 경막 외 카테터를 삽입합니다. </li><li> 포폴 2 ㎎ / ㎏, 펜타닐 150 μg의, 그리고 Rocuronium 0.6 mg의 마취를 유도 / 이전에 삽입 말초 정맥 카테터를 통해 킬로그램. </li><li> Preoxygenate하고 삽관 환자. 세보, 산소 및 공기 (17)와 마취를 유지한다. </li><li> 더블 루멘 중심 정맥 카테터 및 동맥 카테터를 삽입합니다. CVP와 동맥압 (17)를 모니터링합니다. </li></ol> 선박의 간 및 캐 뉼러 2. 분리 <ol><li> 헤파린의 100 IE / kg을 관리하고 예방 적 항생제를 (줄 예를 들어, 트리 메소 프림 80의 160 mg의설파 0 mg)을 얻었다. </li><li> 경피적 Seldinger 기술을 사용하여, 대퇴 정맥에 17 프랑 카테터와 외부 경정맥 (18)에 15 프랑 카테터를 배치합니다. 투시하여 카테터의 위치를​​ 확인합니다. </li><li> 중간 선 아래로 칼 모양의 과정에서 L 자형 절개하여 개복술을 수행 한 후 오른쪽 subcostal 절개 19 일까지 연장. </li><li> 더 간외 전이가 완벽한 검사 및 촉진하여 복부에 없는지 확인합니다. <ol><li> 의심스러운 병변이 발견되면 동결 절편에 의해 악성 종양을 확인합니다. </li><li> 간외 현시 (​​periaortal 병증, 복부 전이)의 증거가있는 경우의 절차를 종료한다. 간 문부에서 림프절 종대는 금기로 간주되지 않습니다. </li></ol></li><li> 낫 인대, 좌우의 삼각 인대 및 관상 인대 (19)를 분할하여 간을 동원. </li><li> caval을 해부하다복막 지류 혈관의 결찰과 다이어프램까지 신장 정맥에서 시작 정맥. </li><li> 오른쪽 부신 정맥을 확인하고 주위 혈관 루프를 배치합니다. </li><li> 오른쪽 성선 정맥을 확인합니다. 5~10cm을 위해 그것을 해부. caval 정맥의 입구 주위에 지갑 문자열 봉합을 놓습니다. <ol><li> 성선 정맥에 원심 합자를 놓습니다. 가위를 사용하여 caval 정맥에서 성선 정맥 3-5cm를 엽니 다. </li><li> 오른쪽 성선 정맥을 통해 18 천을 와이어 강화 카테터를 삽입하고 retrohepatically 신장 정맥 위의 팁을 배치합니다. </li><li> 카테터의 위치를​​ 확보하기 위해 성선 정맥 주위에 합자를 놓습니다. </li><li> 카테터를 통해 혈액의 반환을 확인합니다. 카테터 (18) Heparinize. </li></ol></li><li> hepatoduodenal 인대를 해부하고, 간동맥, 위 십이지장 동맥 적절한 간동맥을 시각화. <ol><li> 장소 용기는 일반적인 간 줄게 주위에 루프공예 및 gastrodoudenal 동맥. </li><li> 포털 정맥을 해부하고 주위 혈관 루프를 배치합니다. </li><li> 담관 함유 인대의 나머지 부분을 분리하고 용기 루프에서이 모두 포함된다. </li></ol></li><li> 선박 루프 위 십이지장 동맥을 들어 올립니다. 동맥 유입을 중단 한 후, 가위를 사용하여 절개를합니다. <ol><li> 적절한 간동맥에 자사의 팁 8-12 프랑 카테터를 삽입합니다. 위 십이지장 동맥 주위에 합자와 위치를 고정합니다. </li><li> 카테터 혈액 반환을 확인하고 그것을 18 다음을 heparinize. </li></ol></li><li> 프라임 적혈구 포장 한 단위, 알부민의 100 ㎖ (50g / L), Tribonat (중탄산 나트륨), 헤파린 2500 단위 (5000 IE / ㎖) 100㎖로 정출 물 250ml를 관류 시스템. </li><li> 동맥 및 롤러 펌프를 구비 심폐 기계 이루어진 관류 시스템 caval 정맥 카테터 및 히터를 연결 t일회용 타입의 혈조, 산화 기 및 배관 시스템과 ogether. </li><li> 히터 유닛과 함께, 원심 펌프로 구성된 정 정맥 바이 패스 펌프 대퇴 및 외부 경정맥 카테터를 연결하고 우회를 시작합니다. </li><li> infrahepatically 신장 정맥 위의 caval 정맥 주위에 Rumel 지혈대를 강화하고 Klintmalm 혈관 클램프를 사용하여 suprahepatically caval 정맥을 체결하여 간의 분리를 완료합니다. <ol><li> 담관, 포털 정맥과 오른쪽 부신 정맥 주위에 Rumel 지혈대를 조이고 마지막으로 혈관 클램프를 사용하여 간동맥을 클램프. </li></ol></li></ol> 3. 관류 <ol><li> 관류를 시작하고 수동으로 혈조의 혈중 농도를 모니터링 할 수 있습니다. 정상 상태 레벨이 500-1,200 ㎖ / 분 사이, 보통의 유량에 도달 할 때까지 유량을 조정한다. </li><li> 오른쪽과 왼쪽 간 엽에 서미스터 프로브를 직접 하나에동맥 카테터. </li><li> C. O 40의 타겟 간 온도를 목표 관류 히트 관류에 걸쳐이 온도를 유지합니다. </li><li> 정 정맥 바이 패스 펌프 머리에 섬광 프로브를 놓습니다. </li><li> 전신 순환으로 10 MBq 내지 99m의 TC-알부민 (1 mL)을 작은 도즈를 주입함으로써, 누설 모니터링 시스템을 보정하고 기준 활성을 등록한다. <ol><li> 간 관류 장치로, 10 배 높은 용량, 100 MBq의의 99m TC-알부민 (1 ml)에 주입한다. </li><li> 섬광 프로브로 측정 활동의 증가로 전신 순환에 관류 시스템에서 누출을 기록합니다. </li><li> 혈조에 볼륨의 증가로 관류 시스템에 전신 순환의 누출을 기록합니다. </li></ol></li><li> 유량의 정상 상태가 확립 될 때의 용량을 주입 멜 팔란, 누설이 존재하지 않으며 간 온도는 40 ° C에 도달관류 시스템에 1 ㎎ / kg (체중) 떨어져 30 분 투여 량으로 주어진 두 나누었다. </li></ol> 4. 관류을 종료하고 카테터를 제거 <ol><li> 관류의 60 분 후, 시스템으로부터 관류를 비우고 정질 1,000 ml로 간 관개. </li><li> 관류 장치에 포장 적혈구의 한 단위를 추가, 간으로 주입 한 후 관류를 중지합니다. </li><li> Klintmalm 클램프 및 caval 정맥에서 Rumel 지혈대를 놓습니다. </li><li> hepatoduodenal 인대에서 Rumel 지혈대를 놓습니다. </li><li> 위 십이지장 동맥에서 합자를 제거합니다. 카테터를 제거하고 혈관을 결찰. </li><li> 간동맥에서 클램프를 놓습니다. </li><li> 성선 정맥 카테터를 제거하고 혈관을 결찰. </li><li> veno 정맥 바이 패스 펌프를 중지하고 튜브를 분리합니다. </li><li> 중단 근막 봉합 한 후 피내 피부 봉합과 복부를 닫습니다. </li><li> C를 제거대퇴 및 외부 경정맥에 atheters과 5 분 동안 현지 압력을 적용합니다. </li></ol> 5. 수술 후 케어 <ol><li> 환자가 튜브를 빼내 24 시간 동안 수술 후 관리 장치에 전송할 수 있습니다. 중심 정맥 압력과 동맥 혈압을 모니터링하십시오. </li><li> 수술 후 치료 3-7 일 일반에 대한 수술 부서에 환자를 전송합니다. </li><li> 4 주 총 5000 IE / 일의 투여 량에서 저 분자량 헤파린 (LMWH) 계속. </li></ol>

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V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hepatic+arterial+chemoembolization+for+management+of+metastatic+melanoma.">Hepatic arterial chemoembolization for management of metastatic melanoma.</a> AJR. American Journal Of Roentgenology. 190 (1), 99-104 (2008).</li><li>Eldredge-Hindy, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Yttrium-90+Microsphere+Brachytherapy+for+Liver+Metastases+From+Uveal+Melanoma:+Clinical+Outcomes+and+the+Predictive+Value+of+Fluorodeoxyglucose+Positron+Emission+Tomography.">Yttrium-90 Microsphere Brachytherapy for Liver Metastases From Uveal Melanoma: Clinical Outcomes and the Predictive Value of Fluorodeoxyglucose Positron Emission Tomography.</a> American Journal Of Clinical Oncology. , (2014).</li><li>Etten, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hypoxic+hepatic+perfusion+with+orthograde+or+retrograde+flow+in+patients+with+irresectable+liver+metastases+using+percutaneous+balloon+catheter+techniques:+a+phase+I+and+II+study.">Isolated hypoxic hepatic perfusion with orthograde or retrograde flow in patients with irresectable liver metastases using percutaneous balloon catheter techniques: a phase I and II study.</a> Annals of Surgical Oncology. 11 (6), 598-605 (2004).</li><li>Ku, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Extracorporeal+adriamycin-removal+following+hepatic+artery+infusion:+use+of+direct+hemoperfusion+combined+with+veno-venous+bypass.">Extracorporeal adriamycin-removal following hepatic artery infusion: use of direct hemoperfusion combined with veno-venous bypass.</a> Nihon Geka Gakkai Zasshi. 90 (10), 1758-1764 (1989).</li><li>Curley, S. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hepatic+arterial+infusion+chemotherapy+with+complete+hepatic+venous+isolation+and+extracorporeal+chemofiltration:+a+feasibility+study+of+a+novel+system.">Hepatic arterial infusion chemotherapy with complete hepatic venous isolation and extracorporeal chemofiltration: a feasibility study of a novel system.</a> Anti-Cancer Drugs. 2 (2), 175-183 (1991).</li><li>Beheshti, M. V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Percutaneous+isolated+liver+perfusion+for+treatment+of+hepatic+malignancy:+preliminary+report.">Percutaneous isolated liver perfusion for treatment of hepatic malignancy: preliminary report.</a> Journal of Vascular And Interventional Radiology : JVIR. 3 (3), 453-458 (1992).</li></ol>

The authors have nothing to disclose.

전이성 포도막 흑색 종 환자는 몇 치료 옵션이 있습니다. 화학 요법 (6), 면역 요법 (23)과 표적 치료 (24)는 개선 된 OS를 보여줄 수 없었다. 약간의 간 전이 환자, 간 절제술은 옵션 (12)이다. 다른 치료는 간 동맥 화학 요법 (HIA) 9, 화학 색전술 (TACE) (25)와 선택적 내부 방사선 치료 (SIRT) (26)를 포함한다. IHP는 주요 복잡한 수...

포도막 흑색 종 발병률은 백인 인구 1에서 가장 높은 인으로, 성인에서 가장 흔한 일차 인공 악성 종양이다. 지역 치료는 안구 적출술 또는 지방 플라크 방사선 치료 2,3로 구성되어 있습니다. 에 관계없이 지역 치료, 전이성 질환은 궁극적으로 환자 4,5의 약 35~50%을 개발할 것입니다. 간은 가장 일반적인 전이 부위와 격리 간전에 존재 환자의 약 50 %이다. 간 전이 환자의 전체 생존 기간의 중앙값 (OS)는 6-12개월 4입니다. 여러 다른 지역 및 전신 치료 전략이 모색되었지만 생존율이 향상되지 않았다. 전신 항암 화학 요법 치료, 모두 단일 물질 (다카 바진 또는 테모 졸로 마이드 6) 또는 조합 치료 (BOLD식이 요법 7, treosulfan 8 젬시 타빈)를 선택한 다음, 이하의 응답 속도를 보여줍니다10 %. 간 동맥 화학 요법 (HIA)는 전신 화학 요법에 비해 약간 높은 반응률하지만, 전체 생존 기간 (9)의 증가없이 보여 주었다. 시스플라틴 (cisplatin) 및 카보 플 라틴 (carboplatin)과 화학 색전술 (TACE)는 9개월 (10)의 중앙 생존 환자의 57 %에서 부분 반응을 보였다. 선택적 내부 방사선 치료 (SIRT)는 7개월 (11)의 중앙 생존 환자의 62 %에서 부분 반응을 보이고있다. 255 명의 환자를 포함하는 간 절제술에 대한 연구에서 14 개월 생존율이보고되었다; 현미경 적 완전 절제가 가능했던 환자의 76, 생존 27개월 (12)이었다. 고립 간 관류 (IHP)는 원래 라이언 Ausman에 의해 개발 된 지역 치료 방법이다. 뒤에 기술의 이론적 근거는 전신적으로 회피하면서 수술 분리 및 화학 요법 제의 투여 량과 높은 간을 관류하는xicity (13). 또한, 동시 고열 종양 혈류 세포막 투과성 (14)의 변화에 의해 화학 요법 제의 증가 된 흡수를 매개한다. 완전한 혈관 아이솔레이션 TC-99은 인간 혈청 알부민 (15)를 이용하여 표지 된 방사성 트레이서 기법으로 확인된다. 후 향적 단계 II 연구는 스웨덴 16 포도막 흑색 종 간 전이 가장 긴 생존자에 비해 IHP을 시행 한 환자 14 개월 (26 대 12개월)의 잠재적 인 생존 이득을 보여 주었다. 여기에서 우리는 현재의 결과와 향후 전망에 대한 간단한 리뷰와 함께 IHP의 기술을 제시한다.

<table><tbody><tr><td>Wire re-inforced catethers</td><td>Medtronic Inc, Minnesota, USA</td><td></td><td>12-18Fr</td></tr><tr><td>St&amp;ouml;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

관류 간 격리 (IHP)는 간이 수술 단리 화학 요법 제의 멜 팔란 고농도 관류 절차이다. 간단히, 절차는 외부 경정맥에 대퇴 정맥에서 경피적 veno 정맥 바이 패스의 설치를 시작합니다. 개복술을 통해, 카테터는 적절한 간동맥 및 caval 정맥에 삽입됩니다. 위의의 뜻과 infrahepatically, 다음 클램핑 모두 문맥과 caval 정맥. 동맥과 정맥 카테터 심폐 기계에 연결되어 간 60 분 동안 멜 팔란 (1 ㎎ / kg 체중)로 관류시켰다. 그것이 가능하다이 방법은 로컬 전신 순환으로 누출하지 않고, 화학 요법 제의 투여 량과 높은 간 관류. 포도막 흑색 종의 고립 간 전이 환자를 포함하여 이전의 연구에서, 33-100%의 전반적인 응답 속도와 9 13개월 사이의 평균 생존 기간,보고되고있다. 이 프로토콜의 목적은 절차를 수행하는 방법의 명확한 설명을 제공하고, 포도막 흑색 종의 간전 대한 치료 옵션으로 IHP을 논의한다.

초기 보고서 또는 TNF-α없이 멜 팔란 치료 22 명을 포함. 결과는 두 CR (10 %)을 가진 환자, 11 개월 (20)의 중앙값을 포함 생존율 62 %의 반응율을 보였다. 후속 연구는 혼자 멜 팔란를 사용하여 치료 29 명의 환자의 결과를보고했다. 결과는 10 % 완전 반응 12 개월 (21)의 중앙 생존 기간을 포함하여 62 % 전체 응답과 매우 유사했다. 로 Rizell 등. 연구에서, 포도막 ?...

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.

포도막 흑색 종의 간전이에 대한 치료로 고립 간 관류

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

Universidad de Cartagena UDEC

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JoVE Journal

Medicine

13.3K 조회수.  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.

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

Murine Model of Metastatic Liver Tumors in the Setting of Ischemia Reperfusion Injury

Liver ischemia and reperfusion (I/R) injury, a common clinical challenge, remains an inevitable pathophysiological process that has been shown to induce multiple tissue and organ damage. Despite recent advances and therapeutic approaches, the overall morbidity has remained unsatisfactory especially in patients with underlying parenchymal abnormalities. In the context of aggressive cancer growth and metastasis, surgical I/R is suspected to be the promoter regulating tumor recurrence. This article aims to describe a clinically relevant murine model of liver I/R and colorectal liver metastasis. In doing so, we aim to assist other investigators in establishing and perfecting this model for their routine research practice to better understand the effects of liver I/R on promoting liver metastases.

We describe in detail a clinically relevant colorectal cancer liver metastases (CRLM) tumor model and the influence of liver ischemia reperfusion (I/R) in tumor growth and metastasis. This model can help to better understand the mechanisms underlying surgery-induced promotion of liver metastatic growth.

허혈 재관류 손상의 설정에서 전이성 간 종양의 뮤린 모델

Liver ischemia and reperfusion (I/R) injury, a common clinical challenge, remains an inevitable pathophysiological process that has been shown to induce ...

연구

암 연구학

Generation of a Liver Orthotopic Human Uveal Melanoma Xenograft Platform in Immunodeficient Mice

In recent decades, subcutaneously implanted patient-derived xenograft tumors or cultured human cell lines have been increasingly recognized as more representative models to study human cancers in immunodeficient mice than traditional established human cell lines in vitro. Recently, orthotopically implanted patient-derived tumor xenograft (PDX) models in mice have been developed to better replicate features of patient tumors. A liver orthotopic xenograft mouse model is expected to be a useful cancer research platform, providing insights into tumor biology and drug therapy. However, liver orthotopic tumor implantation is generally complicated. Here we describe our protocols for the orthotopic implantation of patient-derived liver-metastatic uveal melanoma tumors. We cultured human liver metastatic uveal melanoma cell lines into immunodeficient mice. The protocols can result in consistently high technical success rates using either a surgical orthotopic implantation technique with chunks of patient-derived uveal melanoma tumor or a needle injection technique with cultured human cell line. We also describe protocols for CT scanning to detect interior liver tumors and for re-implantation techniques using cryopreserved tumors to achieve re-engraftment. Together, these protocols provide a better platform for liver orthotopic tumor mouse models of liver metastatic uveal melanoma in translational research.

Orthotopic human liver metastatic uveal melanoma xenograft mouse models were created using surgical orthotopic implantation techniques with patient-derived tumor chunk and needle injection techniques with cultured human uveal melanoma cell lines.

면역결핍 마우스에서 간 직교 인간 편도 흑색종 Xenograft 플랫폼의 생성

In recent decades, subcutaneously implanted patient-derived xenograft tumors or cultured human cell lines have been increasingly recognized as more ...

Portal Vein Injection of Colorectal Cancer Organoids to Study the Liver Metastasis Stroma

Hepatic metastasis of colorectal cancer (CRC) is a leading cause of cancer-related death. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play a crucial role in metastatic CRC progression and predict poor patient prognosis. However, there is a lack of satisfactory mouse models to study the crosstalk between metastatic cancer cells and CAFs. Here, we present a method to investigate how liver metastasis progression is regulated by the metastatic niche and possibly could be restrained by stroma-directed therapy. Portal vein injection of CRC organoids generated a desmoplastic reaction, which faithfully recapitulated the fibroblast-rich histology of human CRC liver metastases. This model was tissue-specific with a higher tumor burden in the liver when compared to an intra-splenic injection model, simplifying mouse survival analyses. By injecting luciferase-expressing tumor organoids, tumor growth kinetics could be monitored by in vivo imaging. Moreover, this preclinical model provides a useful platform to assess the efficacy of therapeutics targeting the tumor mesenchyme. We describe methods to examine whether adeno-associated virus-mediated delivery of a tumor-inhibiting stromal gene to hepatocytes could remodel the tumor microenvironment and improve mouse survival. This approach enables the development and assessment of novel therapeutic strategies to inhibit hepatic metastasis of CRC.

Portal vein injection of colorectal cancer (CRC) organoids generates stroma-rich liver metastasis. This mouse model of CRC hepatic metastasis represents a useful tool to study tumor-stroma interactions and develop novel stroma-directed therapeutics such as adeno-associated virus-mediated gene therapies.

간 전이 스트로마를 연구하기 위해 대장암 오가노이드의 포털 정맥 주사

Hepatic metastasis of colorectal cancer (CRC) is a leading cause of cancer-related death. Cancer-associated fibroblasts (CAFs), a major component of the ...

Technique of Subnormothermic Ex Vivo Liver Perfusion for the Storage, Assessment, and Repair of Marginal Liver Grafts

The success of liver transplantation has resulted in a dramatic organ shortage. In most transplant regions 20-30% of patients on the waiting list for liver transplantation die without receiving an organ transplant or are delisted for disease progression. One strategy to increase the donor pool is the utilization of marginal grafts, such as fatty livers, grafts from older donors, or donation after cardiac death (DCD). The current preservation technique of cold static storage is only poorly tolerated by marginal livers resulting in significant organ damage. In addition, cold static organ storage does not allow graft assessment or repair prior to transplantation.
These shortcomings of cold static preservation have triggered an interest in warm perfused organ preservation to reduce cold ischemic injury, assess liver grafts during preservation, and explore the opportunity to repair marginal livers prior to transplantation. The optimal pressure and flow conditions, perfusion temperature, composition of the perfusion solution and the need for an oxygen carrier has been controversial in the past.
In spite of promising results in several animal studies, the complexity and the costs have prevented a broader clinical application so far. Recently, with enhanced technology and a better understanding of liver physiology during ex vivo perfusion the outcome of warm liver perfusion has improved and consistently good results can be achieved.
This paper will provide information about liver retrieval, storage techniques, and isolated liver perfusion in pigs. We will illustrate a) the requirements to ensure sufficient oxygen supply to the organ, b) technical considerations about the perfusion machine and the perfusion solution, and c) biochemical aspects of isolated organs.

Technique of Subnormothermic Ex Vivo Liver Perfusion for the Storage, Assessment, and Repair of Marginal Liver Grafts

Marginal grafts, such as fatty livers, grafts from older donors, or livers retrieved after cardiac death (DCD) tolerate conventional, cold static storage only poorly. We developed a novel model of subnormothermic ex vivo liver perfusion for preservation, assessment, and repair of marginal liver grafts prior to transplantation.

Subnormothermic의 기술<em&gt; 전의 VIVO</em&gt; 간 스토리지, 평가를위한 관류 및 한계 간 이식의 수리

The success of liver transplantation has resulted in a dramatic organ shortage. In most transplant regions 20-30% of patients on the waiting list for ...

의학

Implantation and Evaluation of Melanoma in the Murine Choroid via Optical Coherence Tomography

Establishing experimental choroidal melanoma models is challenging in terms of the ability to induce tumors at the correct localization. In addition, difficulties in observing posterior choroidal melanoma in vivo limit tumor location and growth evaluation in real-time. The approach described here optimizes techniques for establishing choroidal melanoma in mice via a multi-step sub-choroidal B16LS9 cell injection procedure. To enable precision in injecting into the small dimensions of the mouse uvea, the complete procedure is performed under a microscope. First, a conjunctival peritomy is formed in the dorsal-temporal area of the eye. Then, a tract into the sub-choroidal space is created by inserting a needle through the exposed sclera. This is followed by the insertion of a blunt needle into the tract and the injection of melanoma cells into the choroid. Immediately after injection, noninvasive optical coherence tomography (OCT) imaging is utilized to determine tumor location and progress. Retinal detachment is evaluated as a predictor of tumor site and size. The presented method enables the reproducible induction of choroid-localized melanoma in mice and the live imaging of tumor growth evaluation. As such, it provides a valuable tool for studying intraocular tumors.

Implantation and Evaluation of Melanoma in the Murine Choroid via Optical Coherence Tomography

The present protocol describes the implantation and evaluation of melanoma in the murine choroid utilizing optical coherence tomography.

광간섭 단층촬영을 통한 쥐 맥락막의 흑색종 이식 및 평가

Establishing experimental choroidal melanoma models is challenging in terms of the ability to induce tumors at the correct localization. In addition, ...

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.

간으로 밀폐 절제 불가능한 전이에 대한 치료로 멜 팔란과 경피적 간 관류 (PHP)

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

Visualization of Vascular and Parenchymal Regeneration after 70% Partial Hepatectomy in Normal Mice

A modified silicone injection procedure was used for visualization of the hepatic vascular tree. This procedure consisted of in-vivo injection of the silicone compound, via a 26 G catheter, into the portal or hepatic vein. After silicone injection, organs were explanted and prepared for ex-vivo micro-CT (&#181;CT) scanning. The silicone injection procedure is technically challenging. Achieving a successful outcome requires extensive microsurgical experience from the surgeon. One of the challenges of this procedure involves determining the adequate perfusion rate for the silicone compound. The perfusion rate for the silicone compound needs to be defined based on the hemodynamic of the vascular system of interest. Inappropriate perfusion rate can lead to an incomplete perfusion, artificial dilation and rupturing of vascular trees.
The 3D reconstruction of the vascular system was based on CT scans and was achieved using preclinical software such as HepaVision. The quality of the reconstructed vascular tree was directly related to the quality of silicone perfusion. Subsequently computed vascular parameters indicative of vascular growth, such as total vascular volume, were calculated based on the vascular reconstructions. Contrasting the vascular tree with silicone allowed for subsequent histological work-up of the specimen after &#181;CT scanning. The specimen can be subjected to serial sectioning, histological analysis and whole slide scanning, and thereafter to 3D reconstruction of the vascular trees based on histological images. This is the prerequisite for the detection of molecular events and their distribution with respect to the vascular tree. This modified silicone injection procedure can also be used to visualize and reconstruct the vascular systems of other organs. This technique has the potential to be extensively applied to studies concerning vascular anatomy and growth in various animal and disease models.

Tools used for visualizing vascular regeneration require methods for contrasting the vascular trees. This film demonstrated a delicate injection technique used to achieve optimal contrasting of the vascular trees and illustrate the potential benefits resulting from a detailed analysis of the resulting specimen using &#181;CT and histological serial sections.

일반 마우스의 70 % 부분 간 절제술 후 혈관 및 실질 재생의 시각화

A modified silicone injection procedure was used for visualization of the hepatic vascular tree. This procedure consisted of in-vivo injection of the ...

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.

Ex Vivo Normothermic 간 관류의 작은 동물 모델

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

Isolation of Regenerating Hepatocytes after Partial Hepatectomy in Mice

Partial hepatectomy has been widely used to investigate liver regeneration in mice, but the isolation of high yields of viable hepatocytes for downstream single-cell applications is challenging. A marked accumulation of lipids within regenerating hepatocytes is observed during the first 2 days of normal liver regeneration in mice. This so-called transient regeneration-associated steatosis (TRAS) is temporary but partially overlaps the major proliferative phase. Density-gradient purification is the backbone of most existing protocols for the isolation of primary hepatocytes. As gradient purification relies on the density and size of cells, it separates non-steatotic from steatotic hepatocyte populations. Therefore, fatty hepatocytes often are lost, yielding non-representative hepatocyte fractions. 
The presented protocol describes an easy and reliable method for the in vivo isolation of regenerating hepatocytes regardless of their lipid content. Hepatocytes from male C57BL/6 mice are isolated 24-48 h after hepatectomy by a classic two-step collagenase perfusion approach. A standard peristaltic pump drives the warmed solutions via the catheterized inferior vena cava into the remnant, using a retrograde perfusion technique with outflow through the portal vein. Hepatocytes are dissociated by collagenase for their release from the Glisson's capsule. After washing and careful centrifugation, the hepatocytes can be used for any downstream analyses. In conclusion, this paper describes a straightforward and reproducible technique for the isolation of a representative population of regenerating hepatocytes after partial hepatectomy in mice. The method may also aid the study of fatty liver disease.

Lipid-laden hepatocytes are inherent to liver regeneration but are usually lost upon density-gradient centrifugation. Here, we present an optimized cell isolation protocol that retains steatotic hepatocytes, yielding representative populations of regenerating hepatocytes after partial hepatectomy in mice.

생쥐의 부분 간 절제술 후 재생 간세포의 분리

Partial hepatectomy has been widely used to investigate liver regeneration in mice, but the isolation of high yields of viable hepatocytes for downstream ...

Development and Validation of a Porcine Ex Situ Isolated Liver Perfusion Model 

Porcine Normothermic Isolated Liver Perfusion

Porcine models of liver ex situ normothermic machine perfusion (NMP) are increasingly being used in transplant research. Contrary to rodents, porcine livers are anatomically and physiologically close to humans, with similar organ size and bile composition. NMP preserves the liver graft at near-to-physiological conditions by recirculating a warm, oxygenated, and nutrient-enriched red blood cell-based perfusate through the liver vasculature. NMP can be used to study ischemia-reperfusion injury, preserve a liver ex situ before transplantation, assess the liver's function prior to implantation, and provide a platform for organ repair and regeneration. Alternatively, NMP with a whole blood-based perfusate can be used to mimic transplantation. Nevertheless, this model is labor-intensive, technically challenging, and carries a high financial cost.
In this porcine NMP model, we use warm ischemic damaged livers (corresponding to donation after circulatory death). First, general anesthesia with mechanical ventilation is initiated, followed by the induction of warm ischemia by clamping the thoracic aorta for 60 min. Cannulas inserted in the abdominal aorta and portal vein allow flush-out of the liver with cold preservation solution. The flushed-out blood is washed with a cell saver to obtain concentrated red blood cells. Following hepatectomy, cannulas are inserted in the portal vein, hepatic artery, and infra-hepatic vena cava and connected to a closed perfusion circuit primed with a plasma expander and red blood cells. A hollow fiber oxygenator is included in the circuit and coupled to a heat exchanger to maintain a pO2 of 70-100 mmHg at 38 &#176;C. NMP is achieved by a continuous flow directly through the artery and via a venous reservoir through the portal vein. Flows, pressures, and blood gas values are continuously monitored. To evaluate the liver injury, perfusate and tissue are sampled at predefined time points; bile is collected via a cannula in the common bile duct.

The porcine model of liver normothermic machine perfusion (NMP), described here, can be successfully used to study NMP as a preservation strategy, a tool for viability assessment, and a platform for organ repair. It holds a high translational value, however it is technically challenging and labor-intensive.

Porcine models of liver ex situ normothermic machine perfusion (NMP) are increasingly being used in transplant research. Contrary to rodents, porcine ...