ALPPS一期术后肝内干/祖细胞的变化及其与肝再生的关系

目的:探讨肝内干/祖细胞在联合肝脏分割和门静脉结扎二步肝切除术(ALPPS)一期手术后肝再生中的作用。方法:将72只SD大鼠随机均分为ALPPS组、门静脉结扎(PVL)组和假手术组,分别行ALPPS一期手术、单纯PVL和假手术。分别在术后1、2、3、7 d检测各组血清转氨酶、炎症因子水平与肝右中叶肝再生率(HRR),并检测肝脏组织中细胞增殖指标Ki-67与肝内卵圆细胞(干/祖细胞)标志物OV-6表达水平。结果:与假手术组比较,ALPPS组与PVL组术后1~2 d的转氨酶与炎症因子水平均明显升高,且在ALPPS组的升高水平均大于PVL组(均P0.05);ALPPS组与PVL组术后肝右中叶HRR及肝组织Ki-67阳性率明显升高,但ALPPS组在术后3、7 d的HRR明显高于PVL组,术后2、3 d的Ki-67阳性率明显高于PVL组(均P0.05);ALPPS组与PVL组术后肝组织均有明显OV-6表达,但ALPPS组术后2、3 d的OV-6表达水平明显高于PVL组(均P0.05)。结论:ALPPS一期手术诱导的肝再生明显优于PVL,机制可能为ALPPS术后较高的炎症状态使激活肝内干/祖细胞的动员和活化,从而促进快速肝再生有关。     

ALPPS术后肝再生与内质网应激IRE1α-XBP1通路的关系研究

目的探讨内质网应激在联合肝脏分割和门静脉结扎二步肝切除术(ALPPS)一期手术后肝再生过程中的作用。方法将72只C57bl/6小鼠随机均分为ALPPS组、门静脉结扎组(PVL组)和假手术组(Sham组),每组24只,分别行ALPPS一期手术、单纯PVL和假手术。3组小鼠分别在术后第1、2、4及7天各取材6只,检测各组小鼠的肝重体质量比,并取肝脏组织行免疫组织化学染色以计算Ki-67阳性细胞比,行Western blot法以检测肌醇酶1α(IRE1α)和X盒连接蛋白1(XBP1)蛋白的表达水平。结果 (1)肝重体质量比:术后第4天和第7天时,同时点下Sham组、PLV组和ALPPS组的肝重体质量比依次增加,3组间两两比较差异均有统计学意义(P0.05)。(2) Ki-67阳性细胞比:术后第2天时,Sham组、PLV组和ALPPS组的Ki-67阳性细胞比依次增加,3组间两两比较差异均有统计学意义(P0.05);术后第4天时,ALPPS组与PVL组的Ki-67阳性细胞比仍高于Sham组(P0.05)。(3) XBP1和IRE1α的表达水平:术后第2天和第4天时,与Sham组和PVL组比较,ALPPS组的XBP1和IRE1α的表达水平均较高(P0.05);术后第7天时,与Sham组比较,ALPPS组的XBP1和IRE1α的表达水平较高(P0.05);与PVL组比较,ALPPS组的XBP1的表达水平较高(P0.05)。结论在小鼠体内ALPPS术式诱导的肝再生较传统的PVL术式引起的肝再生更具有优势,这可能是因为ALPPS术后更为明显的内质网应激激活状态,导致IRE1α-XBP1的表达上调,从而参与了肝细胞细胞周期的调控,进而促进了肝细胞的增殖,促进了快速肝再生。     

肝癌大鼠部分门静脉结扎术后血流动力学变化与不同肝叶肿瘤生长的关系

目的 探讨门静脉结扎术(PVL)后,肝脏血流动力学变化与荷瘤大鼠不同肝叶肿瘤生长的关系.方法 将18只雄性大鼠随机分为A、B组.均为荷瘤大鼠,A组行PVL术,B组为假手术组.分别于术后不同时间段,应用多普勒超声测量结扎肝叶与非结扎肝叶肝动脉及门静脉血流速度,正电子发射计算机断层显像(PET-CT)测算结扎与非结扎肝叶上肿瘤的体积变化,分析血流变化与肿瘤体积变化是否存在相关性.结果 A组PVL肝叶肝动脉血流速度明显高于B组[(4.34±0.53) ml/min比(2.07±0.04) ml/min,P＜0.05],且与结扎肝叶肿瘤体积增加呈正相关(r=0.908,P＜0.05).结论 PVL肝叶的肝动脉血流增加是PVL术后结扎侧肝叶肿瘤生长加速的促进因素.     

门静脉阻断对原发性肝癌荷瘤大鼠不同肝叶肿瘤生长的影响

目的 观察在门静脉阻断术(PVL)后荷瘤大鼠不同肝叶肿瘤的生长.方法 将27只雄性大鼠平均分为3组.A组为无荷瘤大鼠,B、C组为荷瘤大鼠.A组(对照组)和C组(实验组)大鼠行PVL术,B组为假手术组.分别于术后不同时段,应用正电子发射计算机断层显像(PET-CT)测算不同肝叶上肿瘤生长的体积变化及肿瘤生长率.结果 C组门静脉结扎肝叶上的肿瘤体积增生明显高于B组[ (54.90±32.17) mm3比(28.41±11.04) mm3,P＜0.05],而无门静脉结扎肝叶上的肿瘤体积增生及肿瘤生长率差异无统计学意义(P＞0.05).结论 PVL术可加速大鼠门静脉结扎肝叶上肿瘤的生长,但不会促使无门静脉结扎肝叶上肿瘤生长的加速.     

不同肝实质劈离方式对大鼠门静脉结扎术后预留肝脏增生的影响

目的探讨肝实质劈离在促进门静脉部分结扎(PVL)大鼠预留肝脏(FLR)再生中的作用和机制。方法用随机数字表法将健康成年Sprague-Dawley(SD)大鼠分为PVL组、PVL+肝实质完全劈离(ALPPS)组、PVL+肝实质部分劈离(PVL+PLP)组、PVL+结扎侧肝叶劈离组(PVL+PLL)、PVL+脾脏射频消融组(PVL+RFA)和假手术组(Sham), 术后按1、3、5、7 d共4个时相点分别处死动物采取标本, 每一时相点4只大鼠, 每组共16只大鼠。分别测定预留肝脏质量和门静脉压力, 酶联免疫吸附试验(ELISA)检测血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBIL)、白蛋白(ALB)和肝再生相关细胞因子(HGF)、白细胞介素-6(IL-6)、肿瘤坏死因子α(TNF-α)水平, 免疫组织化学检测细胞增殖核抗原(Ki-67)及磷酸化组蛋白H3(pH3)的表达并计算阳性率。计量资料以均数±标准差表示, 多组均数间的比较采用One-way ANOVA分析, 组间采用最小显著差异法(LSD法)行两两比较。结果 PVL+PLP组的FLR质量与体重之比(RML/BW)...     

异位劈离联合门静脉结扎对大鼠肝脏再生的影响北大核心CSCD

目的探讨异位劈离联合门静脉结扎对大鼠肝脏再生的影响。方法60只SD大鼠随机分为4组：门静脉结扎组（PVL组）、联合肝脏离断和门静脉结扎组（ALPP组）、脾脏劈离联合门静脉结扎组（ASPP组）和肾脏劈离联合门静脉结扎组（AKPP组）,分别于术后第2、4、7天检测右中叶肝再生率,ALT、AST和肝细胞增殖细胞核抗原（PCNA）标记表达数量。结果ALPP组、ASPP组、AKPP组与PVL组比较,术后第4、7天肝右中叶显著增生（F=3．750,P〈0．05;F=16．398,P〈0．01）,肝组织PCNA阳性表达数术后第4、7天显著增高（F=6．860,P〈0．01;F=3．810,P〈0．05）。ALPP组与其余三组比较。血清ALT和AST浓度术后第2、4天显著增高（ALT：分别F=8．812,21．929;AST：分别F=36．393,6．468;P〈0．01）。ASPP组、AKPP组与ALPP组比较,术后肝右中叶增生率、肝组织PCNA阳性表达数差异无统计学意义。结论异位劈离联合门静脉结扎与联合肝脏离断和门静脉结扎均可显著促进大鼠肝脏再生。而大鼠肝脏再生机制可能与肝脏、脾脏或肾脏的离断所引发的炎症反应、应激反应以及通过特定通路促使某些细胞因子高表达有关。     

一种大鼠选择性门静脉分支结扎模型的建立

目的 在显微镜辅助下建立一种大鼠选择性门静脉分支结扎(sPVL)模型,观察其对肝再生的影响.方法 模型组选择性结扎70％的门静脉;假手术组仅游离门静脉但不结扎.评估各组肝功能、肝脏指数、肝再生率和肝脏组织病理学改变.结果 30只大鼠成功实施sPVL手术.术后14 d,模型组未结扎叶肝脏指数达(90.36 ±0.21)％,与假手术组(34.39±2.50)％比较,差异有统计学意义(P＜0.01).结扎叶肝脏逐渐萎缩.谷丙转氨酶(ALT)水平于术后48 h达到峰值[(454.33±116.00) U/L],术后第7天回落至术前水平[(59.67 ±9.00) U/L].总胆红素(TBIL)和血清白蛋白水平无明显变化.与假手术组比较,组织病理学染色示未结扎叶肝细胞体积增大,肝血窦明显增宽,中央静脉周围及汇管区均无明显胶原沉积;而结扎叶肝细胞明显萎缩,后期出现广泛的胶原沉积.结论 成功建立有效促进残肝再生的鼠sPVL模型,且该方法稳定可靠、重复性好.     

术前门静脉闭塞对于超越门静脉闭塞侧肝叶切除术的优点

术前门静脉栓塞术可使未被栓塞的肝叶代偿肥大,能提高残留肝的功能,为了证实上述观点,取Wis－tar鼠作实验,随机分成3组：门静脉结扎一肝切除组（PVL－H）在全麻下部腹．结扎供应左外侧叶和中叶的门静脉支,另两个对照组同样显露门静脉支但不予结扎（NPVL组）。7天后,3组反映肝功能的一系列指标基本达到平衡,均无明显差异,此时进行第二次手术。PVL－H组与NPVL－88％肝切除组（NPVL－88％）均切除88％肝组织,即肝左外侧叶、中叶和右外侧叶,仅留下层叶,NPVL－67％肝切除组（NPVL－67％）仅切除肝左外侧叶和中叶。整个实…     

转化生长因子α和β1在极限门静脉结扎肝脏组织中的表达及其意义

目的探讨转化生长因子（TGF）-α和TGF-β1在90%极限门静脉分支结扎大鼠肝脏组织中的表达及其与肝脏再生的关系。方法 SD雄性大鼠96只,随机平均分成假手术组和门静脉结扎（PBL）组,观察术后0.5、1、3、5、7、14、21和28d总肝脏和未结扎侧肝脏质量变化,光学显微镜下观察未结扎侧肝细胞的形态变化,用免疫组化方法检测未结扎侧肝细胞的增殖细胞核抗原（PCNA）及TGF-α和TGF-β1的表达。结果 90%极限门静脉分支结扎后,结扎侧肝叶呈进行性萎缩、变小,未结扎侧肝叶占总肝质量的比例在术后1d内增加较缓慢,而在术后1～5d增加速度明显加快,5d以后增加变慢,于7d达＂平台期＂。与假手术组比较,PBL组术后肝组织中PCNA表达在术后0.5～3d明显增多（P〈0.01）,术后5d达高峰,7d有所减少,但仍高于假手术组（P〈0.01）,以后减少接近假手术组。假手术组术后肝脏可见少量TGF-α和TGF-β1表达,PBL组大鼠未结扎侧肝叶术后0.5d开始两者表达量增加,分别至术后3d和1d达高峰（P〈0.05）,术后7～28d下降并接近假手术组（P〉0.05）。结论大鼠90%PBL术后导致未结扎侧肝脏再生,而TGF-α和TGF-β1蛋白表达与肝脏再生启动和增殖过程密切相关。     

术前门静脉分支闭塞与肝切除后功能的关系

广泛切除肝叶超越其残留肝功能时可增加肝衰竭的危机，为了克服这一危机可采用术前门静脉分支栓塞术，在动物实验和临床已证实门静脉结扎例肝叶萎缩，而门静脉未结扎侧肝叶代偿肥大，以往仅着重门静脉分支结扎（PBL）后际体积的变化，作者进一步研究肝劫能的改变。取Wistar鼠，在麻醉下剖腹，用4－0丝线结扎供应左肝外侧叶和中叶的门静脉支。假手术组同样显露门静脉支但不结扎。2天后两组均切除肝左外侧叶和中叶。在第3组，仅切除肝左外侧叶和尾叶。在肝切除当天和肝切除后1、2、3、7天再次剖腹，切除不足0．1g肝组织作腺嘌呤核苷酸测定，…     

Hepatic regeneration by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is feasible but attenuated in rat liver with thioacetamide-induced fibrosis

Background

The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure promotes the proliferation of the future liver remnant, but evidence to support the feasibility of ALPPS in livers with fibrosis is needed. Therefore the aim of this study was to establish a fibrotic ALPPS model in the rat to compare the capacity of regeneration in the remnant liver with or without fibrosis.

The ALPPS technique for bilateral colorectal metastases: three “variations on a theme”

The aim of this study was to assess feasibility of technical variations of the associating liver partition and portal vein ligation for staged hepatectomy technique (ALPPS) with regard to three different ways of liver splitting. The ALPPS technique was applied in the classic form consisting in ligation of the right portal vein, limited resections on the left lobe and splitting along the umbilical fissure; the right lobe was removed 1 week later. The first variation was “left ALPPS”: ligation of the left portal vein, multiple resections on the right hemiliver and splitting along the main portal fissure. The second variation was “rescue ALPPS”, consisting in simple splitting of the liver along the main portal fissure several months after a radiological portal vein embolization that did not allow satisfactory liver hypertrophy. The third variation was “right ALPPS”, consisting in ligation of the posterolateral branch of right portal vein, left lateral sectionectomy, multiple resections on the right anterior and left medial section and splitting along the right portal fissure. In all cases auxiliary deportalized liver was removed 1 week later. 4 patients with colorectal metastases were included. Morbidity was defined according to the Clavien–Dindo classification: grade I (2 events), grade IIIb (1 event). Postoperative mortality was nil. Median follow-up was 4 months and to date all patients are still alive. ALPPS technique, in its “classical” and modified forms, is a good option for selected patients with bilateral colorectal metastases and represents a feasible alternative to classical two-stage hepatectomy.     

Two-Staged Procedure of Portal Ligation and Hepatectomy Monitored by ICG Clearance

Background: The aim of the study was to predict and estimate the optimal time of resection following portal vein ligation (PVL) with the aid of three dimensional (3D) computed tomography (CT) volumetry and indocyanine green (ICG) clearance in healthy liver. Following right PVL, we induced hypertrophy of the left liver lobe prior to an extended right hepatectomy. Methods: Fourteen patients with right lobe liver metastases from colorectal cancer underwent right PVL. Cutoff points for the ICG clearance test were: R15 < 14% or PDR > 15%/min. The criteria for resection also required a remnant liver volume of 25% of the whole liver volume. The latter was assessed by CT scan prior to the procedures. Liver function was measured with routine biochemical tests and ICG clearance. Postoperatively, repeated ICG clearance and 3D CT volumetry tests were used to estimate the liver's regeneration. Liver resections were performed as a second stage. Results: After portal ligation, ICG clearance increased significantly in some patients, while in others, the ICG clearance remained unchanged with borderline low or normal clearance values. Between the two operations, patients with high clearance had less complications and a better regeneration rate of the left lobe with a shorter waiting period in contrast to the “low ICG group.” Conclusions: ICG clearance has a significant prognostic value. Patients with an apparently inoperable right lobe liver tumor can be successfully treated using a two-staged procedure of portal vain ligation followed by hepatectomy. The 3D CT volumetry and ICG clearance test are essential monitoring tools in these liver resections.     

联合肝脏分隔和门静脉结扎的二步肝切除术临床与基础研究进展

联合肝脏分隔和门静脉结扎的二步肝切除术（ALPPS）由德国Hans Schlitt教授在2007年首创,即通过Ⅰ期手术时结扎肝脏荷瘤侧肝叶的门静脉分支,同时分隔荷瘤侧和健侧肝组织,使健侧肝脏在1~2周内快速再生,待健侧肝脏增生足够时,Ⅱ期手术切除荷瘤侧肝脏,可使相当一部分原本不能手术切除的肝癌患者重新获得根治性切除的机会。ALPPS效果显著,相对于门静脉栓塞可更快速地诱导肝脏再生,并且随着手术经验的积累和外科技术的改良,ALPPS术后并发症率明显降低,越来越多地应用于原发性和继发性肝脏肿瘤的治疗,包括结直肠癌肝转移、肝细胞癌和肝内胆管癌等。ALPPS自创立以来,其临床改良术式不断涌现,包括基本手术技术和技巧的改进、肝脏分隔的微创改进、门静脉结扎的微创改进、手术入路的微创改进和经导管动脉栓塞术补救性ALPPS等。ALPPS诱导肝再生过程中肝脏免疫微环境可发生明显的变化,但关键免疫组分的作用、肝再生的空间起源、分布及其亚群特征等仍有待明确。目前,ALPPS对肝脏肿瘤的具体影响及其机制并不完善,仍需进一步探索和证实。ALPPS的临床应用前景广阔,相关机制研究的转化也有望为临床主动诱导肝再生和肝功能衰竭的防治提供新的思路。     

Rapid Liver Hypertrophy After Portal Vein Occlusion Correlates with the Degree of Collateralization Between Lobes—a Study in Pigs

Background

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces more rapid liver growth than portal vein ligation (PVL). Transection of parenchyma in ALPPS may prevent the formation of collaterals between lobes. The aim of this study was to determine if abrogating the formation of collaterals through parenchymal transection impacted growth rate.

Methods

Twelve Yorkshire Landrace pigs were randomized to undergo ALPPS, PVL, or “partial ALPPS” by varying degrees of parenchymal transection. Hepatic volume was measured after 7 days. Portal blood flow and pressure were measured. Portal vein collaterals were examined from epoxy casts.

Results

PVL, ALPPS, and partial ALPPS led to volume increases of the RLL by 15.5% (range 3–22), 64% (range 45–76), and 32% (range 18–77), respectively, with significant differences between PVL and ALPPS/partial ALPPS (p < 0.05). In PVL and partial ALPPS, substantial new portal vein collaterals were found. The number of collaterals correlated inversely with the growth rate (p = 0.039). Portal vein pressure was elevated in all models after ligation suggesting hyperflow to the portal vein-supplied lobe (p < 0.05).

Conclusions

These data suggest that liver hypertrophy following PVL is inversely proportional to the development of collaterals. Hypertrophy after ALPPS is likely more rapid due to reduction of collaterals through transection.

     

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??Portal vein ligation versus portal vein embolization for hepatectomy??A Meta-analysis SONG Wei??ZOU Shu-bing. Department of Hepatobiliary Surgery??the Second Affiliated Hospital of Nanchang University??Nanchang 330000??China
Corresponding author??ZOU Shu-bing??E-mail??zousb999@163.com
Abstract Objective To systematically review the growth rate in future liver remnant (FLR) and perioperative outcomes after portal vein ligation (PVL) and portal vein embolization (PVE) before hepatectomy. Methods Such databases as MEDLINE, EMBASE, PubMed, Cochrane Library, CNKI, VIP, WanFang Data were electronically searched for randomized controlled trials (RCTs) or clinical controlled trials (CCTs) on application of portal vein ligation versus portal vein embolization for staged hepatectomy. The meta-analysis was performed using RevMan 5.3 software. Results A total of 8 studies were included with a total of 438 patients. The results of meta-analysis showed that??There was no difference in the increasement in FLR between PVE group versus PVL group??RR=6.04??95%CI??-0.23—12.32??P> 0.05). Similarly??there was no difference in the interval time??complications after PVE/PVL?? progression diseased after PVE/PVL??mortality??postoperative liver failure??morbidity and resectability in the two groups after hepatectomy. However??in a subset analysis comparing FLR with PVE and PVL??there was a significant increasement in FLR in favor of ALPPS??RR=30.14??95%CI??4.84—55.44??P< 0.05). Conclusion PVL and PVE for staged hepatectomy have a similar growth rate in FLR??mortality and morbidity rates in the hepatectomy. The ALPPS procedure results in an improved growth rate in FLR compared with PVE.     

联合肝脏离断和门静脉结扎的二步肝切除术治疗肝硬化巨大肝癌2例报告并文献复习

目的:探讨联合肝脏离断和门静脉结扎的二步肝切除术(ALPPS)治疗肝硬化巨大肝癌的安全性及有效性。方法:回顾性分析2014年8月和2015年1月东南大学附属中大医院行ALPPS治疗的2例合并肝硬化的右肝巨大肝癌患者的临床资料,通过围手术期指标和术后随访资料评价疗效。结果:2例患者第一步手术行门静脉右支结扎和左右半肝原位劈离,第一步手术后2例患者的剩余肝体积均迅速增大,患者1术后6 d,剩余肝体积达到704.8 m L,占标准肝体积的60.3%;患者2术后11 d,剩余肝体积达到771.3 m L,占标准肝体积的63.6%。2例患者第二步手术行扩大右半肝切除术。第一步手术时间分别为240 min和210 min,术中出血均为600 m L;第二步手术时间为300 min和325 min,术中出血为1000 m L和800 m L。围手术期无死亡及术后严重并发症发生。术后随访6个月,均无新发肝内外转移。结论:ALPPS治疗肝硬化巨大肝癌是安全可行的。     

Portal vein embolization vs. portal vein ligation for induction of hypertrophy of the future liver remnant

The objective of this study was to assess the efficacy of right portal vein embolization (PVE) vs. right portal vein ligation (PVL) for induction of hypertrophy of the left lateral liver lobe before extended right hepatectomy. Thirty-four patients with primary or secondary liver tumors and estimated remnant functional liver parenchyma of less than 0.5% of body weight underwent either right PVE (transcutaneous, n= 10; transileocolic, n =7) or right PVL (n=17). Liver volume was assessed by CT scan before occlusion of the right portal vein and prior to resection. There were no deaths. The morbidity rate in each group was 5.8% (PVE, 1 abscess; PVL, 1 bile leak). The increase in liver volume was significantly higher after PVE compared with PVL (188±81 ml vs. 123±58 ml) (P= 0.012). Postoperative hospital stay was significantly shorter after PVE in comparison to PVL (4±2.9 days vs. 8.1±5.1 days;P<0.01). Curative liver resection was performed in 10 of 17 patients after PVE and 11 of 17 patients after PVL. PVE and PVL were found to be feasible and safe methods of increasing the remnant functional liver volume and achieving resectability for extended liver tumors. PVE results in a significantly more efficient increase in liver volume and a shorter hospital stay. Presented at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, California, May 19–22, 2002 (oral presentation).     

门静脉结扎与栓塞在肝切除术中应用的Meta分析

目的 系统评价门静脉结扎（PVL）和门静脉栓塞（PVE）后肝切除前剩余肝体积（FLR）增长率和其他围手术期结局指标。方法 检索相关数据库,收集关于PVL与PVE在肝切除术中应用的随机对照试验（RCT）或临床对照试验（CCT）,提取相关数据后,采用RevMan5.3软件进行Meta分析。结果 最终纳入8项研究,共438例病人。Meta分析结果显示：PVE组与PVL组FLR增长率、术后病死率、肝功能衰竭和并发症等方面差异无统计学意义。然而,联合肝脏分隔和门静脉结扎的二步肝切除术（ALPPS）较PVE能明显增加FLR。结论 PVL与PVE在肝切除术中有着相似的FLR增长率、术后病死率和并发症。ALPPS 相比PVE能明显加速FLR增长。