白细胞介素-6与联合肝脏分隔和门静脉结扎的二步肝切除术后剩余肝脏体积增生的相关性研究

Correlation between interleukin-6 and future liver remnant growth after associating liver partition and portal vein ligation for staged hepatectomy

目的:探讨外周血白细胞介素-6(IL-6)变化与联合肝脏分隔和门静脉结扎的二步肝切除术(ALPPS)后剩余肝脏体积(FLR)增生的相关性。方法:采用回顾性横断面研究方法。收集2017年3月至2018年5月广西医科大学第一附属医院收治的15例行ALPPS患者的临床病理资料。观察指标:(1)术中情况:① ALPPS一期手术。②ALPPS二期手术。(2)术后情况:①术后并发症及住院时间。②术后病理学检查结果。(3)术前、术后外周血IL-6浓度。(4)随访情况。采用门诊、电话及互联网方式进行随访,随访内容包括患者生命质量和生存情况,影像学检查结果了解肿瘤复发或转移情况,随访时间截至2018年 5月。正态分布或近似正态分布的计量资料以±s表示,偏态分布的计量资料采用M(范围)表示,重复测量数据采用重复测量方差分析。相关性比较采用Pearson双变量相关性检验。结果:(1)术中情况, ①ALPPS一期手术:15例患者均采用前入路联合选择性肝静脉阻断技术进行肝实质离断隔离,手术时间为324 min(240~387 min);术中出血量为356 mL(200~600 mL),均未输异体血;术后16 d FLR为(582± 134)cm3;与ALPPS二期手术间隔时间为24 d(9~34 d);肝体积增生率为35%±20%;FLR/标准肝体积(SLV)为53%±7%。②ALPPS二期手术:15例患者中,13例顺利施行二期手术,11例行保留肝中静脉的右半肝切除术,2例未保留肝中静脉行扩大右半肝(右三叶)切除术;1例因FLR/SLV=31%,未达到安全切除标准,行经导管动脉内化疗栓塞(TACE)治疗后出院;1例二期手术中见左半肝表面米粒样黄白结节,术中冷冻切片病理学检查示肝细胞癌,予5氟尿嘧啶腹腔局部化疗联合术后TACE治疗后好转出院。13例施行ALPPS二期手术患者手术时间为324 min(140~515 min);术中出血量为639 mL(100~1 400 mL);2例术中输血治疗,其中1例输注新鲜冰冻血浆800 mL、红细胞4.0 U,1例输注血浆600 mL、去白细胞和红细胞9.5 U。(2)术后情况。①术后并发症及住院时间:15例患者未发生围术期死亡,一期手术后肝衰竭 A级9例、B级6例,Clavien-Dindo术后并发症分级Ⅰ级15例,无Ⅱ级以上并发症,胸腔积液10例(1例积液量>500 mL)。13例行ALPPS二期手术患者,术后肝衰竭A级4例、B级9例,Clavien-Dindo术后并发症分级Ⅰ级8例、Ⅱ级5例,无Ⅲ级以上患者,少量胸腔积液11例(积液量<500 mL)。B级肝衰竭和Ⅱ级并发症患者予加强护肝、护胃、加强换药、连续使用白蛋白或输注新鲜冰冻血浆等治疗后均康复出院。积液量>500 mL的胸腔积液患者经胸腔闭式引流后好转,其余胸腔积液经对症支持治疗后好转。15例患者总住院时间为31 d(22~49 d)。②术后病理学检查结果:13例完整施行ALPPS患者均为肝细胞癌,外科切缘未见癌细胞累及均为R0切除,其中7例存在Ⅱ级门静脉癌栓。15例患者Ishak术后病理学纤维化或肝硬化评分为(7.7±1.4)分,其中5分1例,6分1例,7分2例,8分6例,9分5例。(3)术前术后外周血IL-6浓度:15例患者行ALPPS一期手术前外周血IL-6浓度为(8±3)ng/L,ALPPS一期手术后第1、3、5、7、10天外周血IL-6浓度分别为(207±150)ng/L、(104±65)ng/L、(45±38)ng/L、(26±9)ng/L、(18±10)ng/L,外周血IL-6浓度术前、术后变化趋势比较,差异有统计学意义(F=25.877,P<0.05);术后第1、3、5、7、10天分别与术前比较,差异均有统计学意义(P<0.05)。ALPPS一期手术后第1、3天外周血IL-6浓度与FLR增生量存在明显相关性(r=0.766,0.881,P<0.05),与增生率也存在明显相关性(r=0.810,0.879,P<0.05)。(4)随访情况:15例患者均获得随访,随访时间为1~14个月,中位随访时间为7个月。15例患者中,1例未行ALPPS二期手术患者术后7个月死于全身多器官衰竭。14例患者生存,随访期间生活均能自理,生命质量改善,其中1例行完整ALPPS患者二期手术后12个月肺部多发转移,甲胎蛋白(AFP)轻度升高;13例腹上区增强CT及肝脏超声造影检查均未发现剩余左半肝新发病灶,AFP正常。结论:ALPPS一期手术后外周血第1、3天IL-6峰值与术后FLR的增生存在明显相关性,可预测术后FLR的增生情况。

Objective:To investigate the correlation between interleukin-6 (IL-6) and future liver remnant (FLR) growth after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Methods:The retrospective cross-sectional study was conducted. The clinicopathological data of 15 patients who underwent ALPPS at the First Affiliated Hospital of Guangxi Medical University between March 2017 and May 2018 were collected. Observation indicators: (1) intraoperative situations in the first staged ALPPS and the second staged ALPPS; (2) postoperative situations: ① postoperative complications and duration of hospital stay, ② results of pathological examination; (3) IL-6 concentration in the peripheral blood before and after operation; (4) followup situations. Followup using outpatient examination, telephone interview and internet was performed to detect life quality and survival of patients. Imaging examination was done to detect tumor recurrence and metastasis. Followup was done up to May 2018. Measurement data with normal distribution or similar normal distribution were represented as ±s. Measurement data with skewed distribution were described as M (range). Repeated measures data were analyzed by the repeated measures ANOVA. Correlation comparison was done using Pearson bivariate correlation test. Results:(1) Intraoperative situations. ① The first staged ALPPS: 15 patients had liver parenchymal transection via anterior approach combined with selective hepatic vascular exclusion, without allogenic blood transfusion. The operation time, volume of intraoperative blood loss, FLR at postoperative 16 days, interval time to the second staged ALPPS, growth rate of liver volume, ratio of FLR and standard liver volume (SLV) were respectively 324 minutes (range, 240-387 minutes), 356 mL (range, 200-600 mL), (582±134)cm3, 24 days (range, 9-34 days), 35%±20% and 53%±7%. ② The second staged ALPPS: of 15 patients, 13 underwent the second staged ALPPS successfully including 11 undergoing middle hepatic vein preserved right hepatectomy and 2 undergoing expanded right hemihepatectomy or right trisegmentectomy, 1 underwent transcatheter arterial chemoembolization (TACE) due to FLR/SLV=31%, 1 was detected yellowwhite nodules at left lobe and confirmed as hepatocellular carcinoma by frozen section pathological examination, and then improved and discharged after 5FU abdominal local chemotherapy combined with postoperative TACE. The operation time, volume of intraoperative blood loss of 13 patients undergoing the second staged ALPPS were 324 minutes (range, 140-515 minutes) and 639 mL(range,100-1 400 mL). Two patients had blood transfusion including 1 with 800 mL of fresh frozen plasma and 4.0 U of red cells and 1 with 600 mL of plasma and 9.5 U of deleucocytes and red cells. (2) Postoperative situations. ① Postoperative complications and duration of hospital stay: 15 patients had no perioperative death, 9 and 6 were detected grade A and grade B liver failure respectively, 15 had grade I complications of ClavienDindo classification and no patient had grade Ⅱ and above complications, 10 had pleural effusion including 1 with volume of effusion >500 mL. Of 13 patients undergoing the second staged ALPPS, 4 and 9 were detected grade A and grade B liver failure respectively, 8 and 5 had grade Ⅰ and Ⅱ complications of ClavienDindo classification and no patient had grade Ⅲ and above complications, 11 had few pleural effusion with volume of effusion <500 mL. Patients with grade B liver failure and grade Ⅱ complications were recovered and discharged after treatments of liver protection, gastric protection, reinforced dressing change, continuous use of Alb, fresh frozen plasma transfusion. The patient with volume of pleural effusion >500 mL was improved after closed thoracic drainage and other patients with pleural effusion were improved after symptomatic and supportive treatment. Duration of total hospital stay was 31 days (range, 22-49 days) in 15 patients. ② Results of pathological examination: 13 patients undergoing complete ALPPS were diagnosed as hepaticocellular carcinoma with R0 resection and without cancer cells involving surgical margin, including 7 with grade Ⅱ portal vein tumor thrombus. Ishak score for postoperative pathological fibrosis and liver cirrhosis was 7.7±1.4 in 15 patients, including 1 case of 5, 1 case of 6, 2 case of 7, 6 case of 8, 5 case of 9. (3) IL-6 concentration in the peripheral blood before and after operation: IL-6 concentration in the peripheral blood before surgery was (8±3)ng/L in 15 patients, and (207±150)ng/L, (104±65)ng/L, (45±38)ng/L, (26±9)ng/L, (18±10)ng/L at 1, 3, 5, 7, 10 days after the first staged ALPPS, showing a statistically significant difference in changing trend before and after surgery (F=25.877, P<0.05) and statistically significant differences in paired comparison between 1, 3, 5, 7, 10 days after the first staged ALPPS and before surgery respectively (P<0.05). There was correlation between IL-6 concentration in the peripheral blood at 1, 3 days after the first staged ALPPS and growth of FLR (r=0.766, 0.881, P<0.05), and also between IL-6 concentration in the peripheral blood at 1, 3 days after the first staged ALPPS and growth rate of FLR (r=0.810, 0.879, P<0.05). (4) Followup: 15 patients were followed up for 1-14 months with a median time of 7 months. Of the 15 patients, 1 without the second staged ALPPS died of multiple organ dysfunction syndrome at 7 months after the first staged ALPPS, 14 survived and took care of theirselves in daily life during followup with improved life quality, including 1 detected multiple lung metastases at 12 months after complete ALPPS with mild increased AFP and 13 undetected new lesions in the remnant liver on contrastenhanced CT and liver contrastenhanced ultrasonography with normal AFP. Conclusion: The peak of IL-6 concentration in peripheral blood at 1, 3 days after the first staged ALPPS is significantly correlated with the hyperplasia of FLR, which may be used to predict the hyperplasia of FLR.