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Clarification of pathogenesis and development of therapeutic strategy for small-for size syndrome after major hepatectomy in biliary tract cancer

胆道癌肝大部切除术后小体积综合征发病机制的阐明及治疗策略的制定

基本信息

批准号：
17390361
负责人：
MIYAZAKI Masaru
金额：
$ 10.11万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390361/
关键词：
biliary tract cancer hepatectomy obstructive jaundice surgical resection liver failure 管切除

项目摘要

(1)Clinical StudyPostoperative hepatic insufficiency is a critical complication after extended hepatic resection in patients with biliary tract malignancies, the majority of whom suffer from obstructive jaundice. The aim of this study was to assess clinical parameters linked to this type of liver dysfunction.Methods : A total of 111 patients were retrospectively reviewed. Patient background, pre- and intra-operative parameters, and a ratio of remnant liver volume/entire liver volume (RLV/ELV) as a volumetric parameter, were compared between patients with and without postoperative hyperbilirubinemia and subsequent fatal outcome.Results : Logistic regression indicated that only RLV/ELV ratio was an independent factor influencing postoperative hyperbilirubinemia, and RLV/ELV ratio and indocyanine green retention rate at 15 minutes (ICG-R15) were factors affecting survival. Patients with RLV/ELV<40% had 7.6 times the risk of postoperative hyperbilirubinemia, while no patients having RLV/EL … More V>40% and ICG-R15<25% died of liver failure.Conclusions : The RLV/ELV ratio was the factor with the greatest impact on liver dysfunction after extended hepatic resection in patients with biliary tract malignancies. To prevent these morbidities, volumetric analysis should be performed in a prospective fashion, and, when necessary, preoperative portal vein embolization, or, if possible, limited hepatic resection should be applied.(2)Experimental StudyThe effects of obstructive jaundice on liver regeneration after partial hepatectomy are not yet fully understood.Methods : Hepatocyte growth factor (HGF), its receptor, c-Met, vascular endothelial growth factor (VEGF) and transforming growth factor-f31 (TGF-β1) mRNA expression in both liver tissue and isolated liver cells were investigated after biliary obstruction (BO) by quantitative reverse-transcription polymerase chain reaction (RT-PCR) using a LightCycler. Immunohistochemical staining for desmin and α-smooth muscle actin (α-SMA) was also studied. Regenerating liver weight and proliferating cell nuclear antigen (PCNA) labeling index, and growth factor expression were then evaluated after 70% hepatectomy with concomitant internal biliary drainage in BO rats or sham-operated rats.Results : Hepatic TGF-β1 mRNA levels increased significantly 14 days after BO, and further increased with length of cholestasis. Meanwhile, HGF and VEGF tended to increase, but was not significant. In cell isolates, TGF-β1 mRNA was found mainly in the hepatic stellate cell (HSC) fraction. Immunohistochemical studies revealed increased number of HSCs (desmin-positive cells) and activated HSCs (α-SMA-positive cells) in portal areas after BO. In a hepatectomy model, liver regeneration was delayed in BO rats, as compared to sham-operated rats. TGF-β1 mRNA was significantly up-regulated up to 48h after hepatectomy, and the earlier HGF mRNA peak was lost in BO rats.Conclusion : BO induces HSCs proliferation and activation, leading to up-regulation of TGF-β1 mRNA and suppression of HGF mRNA in livers. These altered expression patterns may be strongly involved in delayed liver regeneration after hepatectomy with obstructive jaundice. Less

（1）临床研究肝功能不全是胆道恶性肿瘤扩大肝切除术后的严重并发症，其中绝大多数伴有梗阻性黄疸。本研究的目的是评估与这种类型的肝功能dysfunction.Methods：共111例患者进行了回顾性分析的临床参数。患者背景，术前和术中参数，以及残肝体积/整个肝脏体积（RLV/ELV）的比值作为体积参数，在有和没有术后高胆红素血症和随后的致命结局的患者之间进行比较。Logistic回归分析显示，仅RLV/ELV比值是影响术后高胆红素血症的独立因素，RLV/ELV比值和吲哚菁绿色留存率（ICG-R15）是影响存活的因素。RLV/ELV<40%的患者术后发生高胆红素血症的风险是正常人的7.6倍，而无RLV/EL的患者术后发生高胆红素血症的风险是正常人的7.6倍。 ...更多信息结论：RLV/ELV比值是影响胆道恶性肿瘤扩大肝切除术后肝功能损害的最重要因素。为了预防这些疾病，应前瞻性地进行体积分析，必要时，术前门静脉栓塞，或如果可能的话，应进行有限的肝切除术。（2）实验研究梗阻性黄疸对肝部分切除术后肝再生的影响尚不完全清楚。肝细胞生长因子（HGF），其受体，c-Met，采用定量逆转录-聚合酶链反应（RT-PCR）技术检测胆道梗阻（BO）后肝组织和肝细胞中血管内皮生长因子（VEGF）和转化生长因子-f31（TGF-β1）mRNA的表达。使用LightCycler进行转录聚合酶链反应（RT-PCR）。免疫组织化学染色结蛋白和α-平滑肌肌动蛋白（α-SMA）。结果：BO后14 d，肝组织TGF-β1 mRNA表达明显增加，并随胆汁淤积时间延长而增加。HGF、VEGF有升高趋势，但无统计学意义。在细胞分离物中，TGF-β1 mRNA主要在肝星状细胞（HSC）组分中发现。免疫组织化学研究显示BO后汇管区HSC（结蛋白阳性细胞）和活化的HSC（α-SMA阳性细胞）数量增加。在肝切除模型中，与假手术大鼠相比，BO大鼠的肝再生延迟。结论：BO可诱导肝星状细胞增殖和活化，导致肝组织TGF-β 1 mRNA表达上调，HGF mRNA表达下调。这些改变的表达模式可能与梗阻性黄疸肝切除术后延迟的肝再生密切相关。少