New Immunotherapy for hepatocellular carcinoma after hepatectomy

实验研究：采用有丝分裂指数（MI）和溴脱氧尿苷（BrdU）标记指数（LI）检测IL-2对70%去肝东流大鼠肝脏再生的影响。肝切除术后立即使用输注泵通过门静脉连续给予IL-2 （45000 JRU/天）或生理盐水。肝切除术后1、2或4天，各组肝脏重量、血清白蛋白、GPT或Bil均无差异。肝切除术后间隙连接开始消失，并在第2天达到最小值。肝切除术后4天，IL-2治疗组的间隙连接密度明显低于生理盐水治疗组。然而，在肝切除术后6天，所有组的密度恢复到接近术前水平。肝再生过程中连续门静脉输注LI-2可瞬时干扰间隙连接的再现。然而，肝再生或肝功能的其他参数没有差异。结果提示肝切除术后肝内给予IL-2无严重并发症。临床研究：我们对12例肝细胞癌（HCC）患者在肝切除术后14天进行了动脉内联合免疫治疗（ACIT）。ACIT由IL-2、OK-432、阿霉素、环磷酰胺和法莫替丁组成。治疗组3年生存率为100%，未治疗组38例3年生存率为60%。因此，肝切除术后动脉内联合免疫治疗可显著提高HCC患者的生存率。3例HCC患者接受ACIT治疗。切除标本的组织学分析显示肝细胞癌病变周围有大量淋巴细胞浸润。免疫组化分析显示，主要侵袭淋巴细胞为CD8阳性和HLA-DR阳性淋巴细胞。此外，在淋巴细胞浸润区，肿瘤细胞中Fas抗原强烈表达。综上所述，ACIT的抗肿瘤作用可能与激活肿瘤浸润淋巴细胞有关。这些淋巴细胞可能以凋亡的方式杀死肿瘤细胞。少

Experimental study : The influence of IL-2 on liver regeneration was examined using mitotic index (MI) and the bromodeoxyuridine (BrdU) labeling index (LI) in 70% hepatectomized Donryu rats. IL-2 (45,000 JRU/day) or saline was administered continuously via the portal vein immediately after hepatectomy using an infusion pump. No difference in the weight of the liver, serum Alb, GPT,or Bil was observed in any groups at 1,2, or 4 days after hepatectomy. Gap junctions began to disappear after hepatectomy and reached a minimum on day 2 in all groups. Four days after hepatectomy, the density of the reappearing gap junctions was markedly lower in groups treated with IL-2 than in those receiving saline. However, the density returned to close to preoperative levels 6 days after hepatectomy in all groups. Continuous portal infusion of LI-2 transiently disturbed gap junction reappearance during liver regeneration. However, no other parameters of liver regeneration or liver functions differed. The … More se results suggest that intrahepatic IL-2 administration can be performed without serious complications after hepatectomy.Clinical Study : We performed intraarterial combined immunotherapy (ACIT) for 12 paticnts with hepatocellular carcinoma (HCC) 14 days after hepatectomy. ACIT consists of IL-2, OK-432, adriamycin, cyclophosphamide, and famotidine. The 3-year survial rate of treated patients was 100%, while, that of 38 untreated patiens was 60%. Thus, intraarterial combined immunotherapy following hepatectomy significantly improved the survival rate in patients with HCC.Three patients with HCC were treated with ACIT.Histological analysis using the resected specimen revealed massive invasion of lymphocytes around HCC lesions. Immunohistochemical analysis demonstrated that the major invaded lymphocytes were the CD8 positive and HLA-DR positive lymphocytes.Furthermore, in the lymphocyte infiltrating area, the Fas antigen in tumor cells were strongly expressed. In conclusion, the antitumor effect of ACIT may be related with the activation of tumor infiltrating lymphocytes. These lymphocytes may kill tumor cells in an apoptotic fashion. Less