Saiho Ko

The serum interleukin 8 level reflects hepatic mitochondrial redox state in hyperthermochemohypoxic isolated liver perfusion with use of a venovenous bypass

BACKGROUNDnWe have recently developed a simple method of hyperthermochemohypoxic isolated liver perfusion (HILP) as a regional therapy for unrecognized liver micrometastases. However, little is known about the influence of HILP on cytokine production and liver function. We investigated the influence of HILP on interleukin 8 (IL-8) production and the hepatic mitochondrial function and assessed the relationship between these 2 parameters. We also measured the serum tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) levels to examine the involvement of HILP-induced cytokines in the tumor response.nnnMETHODSnSixteen patients with metastatic liver tumors were randomly assigned to undergo hepatectomy with HILP (group A, n = 9) or hepatectomy alone (group B, n = 7). The isolated liver was perfused for 30 minutes with Ringers lactate solution containing chemotherapeutic agents warmed to 42 degrees C to 43 degrees C without oxygenation.nnnRESULTSnThe serum IL-8 levels in group A were markedly increased, with peaks at 3 hours after reperfusion, which was significantly higher than levels in group B (P < .01). In group A the arterial ketone body ratio, which reflects the hepatic mitochondrial redox state, decreased during perfusion and was gradually restored to the preperfusion level 1 hour after reperfusion. However, in group B it decreased during hepatectomy but rapidly recovered 5 minutes after hepatectomy. There was a significant negative correlation between the peak serum IL-8 level and the initial velocity of arterial ketone body ratio recovery for the first 5 minutes after reperfusion r = -0.83, P < .001). The serum TNF-alpha and IL-1 beta were temporarily detected only in 3 of 9 patients in group A.nnnCONCLUSIONSnWe have shown that HILP resulted in augmented IL-8 release but not TNF-alpha and IL-1 beta and that the serum IL-8 level reflects the hepatic mitochondrial redox state. These findings suggest that IL-8 production may be associated with hepatic mitochondrial impairment during ischemia. This work may contribute to new therapeutic strategies not only for hepatic ischemia reperfusion injury but also for metastatic liver tumors.

A Case of Splenic Metastasis from Hepatocellular Carcinoma

症例は55歳の男性で, 平成8年2月前区域を中心とする巨大肝細胞癌に対して拡大右葉切除術施行した. その後, 残肝再発, 両側肺転移を来し, TAEを2度, 肺切除を2度施行した. 平成13年11月脾臓に径2.5cmの腫瘍を認めたため, 精査目的に平成14年1月入院. 腹部超音波検査にて腫瘍は径5cmにまで増大していた. 血管造影上, 腫瘍濃染は認めなかったが, 肝細胞癌脾転移と診断し, 手術を施行した. 腫瘍は大部分が脾被膜に覆われて存在していたが, 一部は横隔膜に浸潤しており, 横隔膜・肝臓の一部も合併切除した. 切除標本においても, 腫瘍はほぼ全体が脾実質内に存在していた. 術後3年経過した現在, 無再発生存中である. 肝細胞癌の単発性脾転移はまれであり予後不良例が多いが, 本症例のように他病変がコントロール可能であれば, 切除により良好な予後が期待できる.

Liposomal FK506 in a Canine Hepatic Allograft Model

FK506 is a potent immunosuppressant in clinical use, and has improved the results of organ transplantation.1,2 However, adverse effects of FK506, including nephrotoxicity and neurotoxicity, restrict the permissible dosage.2,3 Local immunosuppression is a potential approach to reduce the adverse effects of systemic immunosuppression. This attractive option in immunosuppressive therapy has been demonstrated to enhance efficacy while simultaneously alleviating systemic adverse effects.4,5 In order to take advantage of this concept, we developed a liposome-incorporated formulation of FK506. Liposomes are artificially constructed phospholipid vesicles which can be formulated to incorporate a variety of agents, and are preferentially taken up by the reticuloendothelial system (RES) following intravenous administration.6 Since the liver and spleen are primary components of the RES, liposome-incorporated FK506 would target the liver and spleen. Because the liver is the site of the allograft in hepatic transplantation and the spleen is a major lymphoid depot, we hypothesized that local delivery of FK506 to these organs via the liposomal formulation would increase immunosuppressive efficacy. On the other hand, liposomal FK506 would unlikely distribute to the brain and kidney, alleviating the nephrotoxicity and neurotoxicity of FK506. In this chapter, we introduce the pharmacokinetic characteristics and immunosuppressive effects of liposomal FK506.

Intraportal Cyclosporine A in Canine Liver Transplantation

Although the application of cyclosporine (CsA)-based immunosuppre sive regimens in the early 1980s provided dramatic improvements in the results of liver transplantation1, early postoperative complications such as acute rejection and infection are still the major causes of morbidity and mortality.2 In addition, adverse effects of immunosuppressants such as nephrotoxicity due to CsA and deterioration of systemic immune function restrict the permissible dosage of these drugs.1

Agarose-microeneapsulated Islet Xenotransplantation.

Discordant異種膵ラ島移植におけるアガロースマイクロカプセル化 (MC (+)) と15-Deoxyspergualin (DSG) 投与の併用効果につき検討した.雑種成犬単離ラ島を5%アガロースハイドロゲルにて, マイクロカプセル化した.6,000個膵ラ島を糖尿病BALB/cマウス, またはNODマウスの腹腔内に異種移植した.Mc (+) ラ島の平均生着日数はそれぞれ37.8日, 30.6日であり, Mc (-) 群に対し有意の生着延長効果を認めた.Mc (+) に少量のDSG投与を加えることにより, 平均生着日数は76.3日, 75.3日とさらに著明に延長した.Mc (+) 群のマウス抗イヌ抗体価レベルは, DSG投与の有無にかかわらず, 移植後50%以上となる場合も認めたが, 正常血漿糖濃度が維持され, 抗体はMc (+) ラ島に傷害をあたえなかった.アガロースマイクロカプセル化とDSG投与の併用による著明な生着延長効果を認め, 将来の異種ラ島移植におけるバイオ人工膵の有用性を示した.