A novel immune signature to predict the prognosis of patients with hepatocellular carcinoma

Aberrant immunity has been associated with the initiation and progression of cancers such as hepatocellular carcinoma (HCC). Here, we aim to develop a signature based on immune-related genes (IRGs) to predict the prognosis of HCC patients. The gene expression profiles of 891 HCC samples were derived from 4 publicly accessible datasets. A total of 1534 IRGs from Immunology Database and Analysis Portal website were obtained as candidate genes for prognostic assessment. Using least absolute shrinkage and selection operator (LASSO) regression analysis, 12 IRGs were selected as prognostic biomarkers and were then aggregated to generate an IRG score for each HCC sample. In the training dataset (n = 365), patients with high IRG scores showed a remarkably poorer overall survival than those with low IRG scores (log-rank P < .001). Similar results were documented in 3 independent testing datasets (n = 226, 221, 79, respectively). Multivariate Cox regression and stratified analyses indicated that the IRG score was an independent and robust signature to predict the overall survival in HCC patients. Patients with high IRG scores tended to be in advanced TNM stages, with increased risks of tumor recurrence and metastasis. More importantly, the IRG score was strongly associated with certain immune cell counts, gene expression of immune checkpoints, estimated immune score, and mutation of critical genes in HCC. In conclusion, the proposed IRG score can predict the prognosis and reflect the tumor immune microenvironment of HCC patients, which may facilitate the individualized treatment and provide potential immunotherapeutic targets.     

Retrohepatic vena cava deroofing in living donor liver transplantation for caudate hepatocellular carcinoma

The removal of tumor together with the native liver in living donor liver transplantation for hepatocellular carcinoma is challenged by a very close resection margin if the tumor abuts the inferior vena cava. This is in contrast to typical deceased donor liver transplantation where the entire retrohepatic inferior vena cava is included in total hepatectomy. Here we report a case of deroofing the retrohepatic vena cava in living donor liver transplantation for caudate hepatocellular carcinoma. In order to ensure clear resection margins, the anterior portion of the inferior vena cava was included. The right liver graft was inset into a Dacron vascular graft on the back table and the composite graft was then implanted to the recipient inferior vena cava. Using this technique, we observed the no-touch technique in tumor removal, hence minimizing the chance of positive resection margin as well as the chance of shedding of tumor cells during manipulation in operation.     

Palliative chemotherapy for patients with recurrent hepatocellular carcinoma after liver transplantation

Background and Aim:  The majority of patients with post-transplantation recurrence of hepatocellular carcinoma (HCC) have extrahepatic metastases and multifocal lesions. Therefore, they have few treatment options and may not be amenable for local therapy. The safety and efficacy of palliative chemotherapy in this population has not been reported.
Methods:  We retrospectively analyzed 24 patients who received palliative chemotherapy for recurrent HCC after liver transplantation between January 2000 and December 2006 at the Seoul National University Hospital.
Results:  The mean age of patients was 55 years (range 42–70 years). The most commonly used chemotherapeutic regimens were 5-fluorouracil (5-FU)/cisplatin ( n  = 9), which was followed by capecitabine/cisplatin ( n  = 4), 5-FU/mitomycin ( n  = 3), 5-FU/oxaliplatin ( n  = 1), S-1 ( n  = 1), capecitabine ( n  = 1), gemcitabine/oxaliplatin ( n  = 1), gemcitabine/cisplatin ( n  = 1), 5-FU/interferon ( n  = 1) and sorafenib ( n  = 2). The Grade 3/4 hematological toxicity was neutropenia (29.1%), thrombocytopenia (20.9%) and anemia (20.9%). There were no cases of neutropenic fever or bleeding events. The Grade 3/4 non-hematological toxicity included elevation of liver transaminase (8.4%) and jaundice (16.7%). No patient showed an objective response and four patients (16.7%) demonstrated stable disease. The median time to progression was 7.0 weeks (95% CI 5.8–8.2) and the median overall survival was 16.6 weeks (95% CI 10.1–23.1).
Conclusion:  Palliative chemotherapy can be delivered to patients with recurrent HCC after liver transplantation with tolerable toxicity. However, the efficacy to date is not satisfactory. Therefore, more effective systemic chemotherapy is needed for this group of patients.     

Overexpression of galectin-1 is associated with poor prognosis in human hepatocellular carcinoma following resection

Background and Aim: The high expression of the galectin‐1 predicts poor patient outcome in several tumors. The aim of this study was to investigate its prognostic value in patients with hepatocellular carcinoma (HCC) after resection. Methods: Galectin‐1 and tumor‐infiltrating FoxP3⁺ regulatory T cells (Tregs) were validated by tissue microarrays from HCC patients (n = 386) and statistically assessed for correlations with the clinical profiles and the prognosis of the patients. Results: We found that galectin‐1, which was prevalently upregulated in HCC, was significantly associated with tumor invasive characteristics (such as vascular invasion, incomplete encapsulation, poor differentiation, multiple number, and large tumor size). Patients with high galectin‐1 expression had a significantly poorer tumor recurrence (P = 0.025) and overall survival (P = 0.021) than those with low galectin‐1 expression. Even in early‐stage disease, high galectin‐1 expression was also independently associated with shortened survival (P < 0.001) and increased tumor recurrence (P = 0.005). Multivariate Cox proportional hazards analysis showed that galectin‐1 was an independent marker for predicting the poor prognosis of HCC. The galectin‐1 level was positively related to the number of tumor‐infiltrating FoxP3⁺ Tregs (r = 0.416, P < 0.001), and their combination served as a better prognosticator. The postoperative tumor recurrence and survival of HCC patients with galectin‐1^high and FoxP3^high were significantly poorer than the other groups (both P < 0.001). Conclusions: Galectin‐1 might be a new prognostic factor for HCC after resection and could potentially be a high‐priority therapeutic target.     

Prognosis following non‐surgical second treatment in patients with recurrent hepatocellular carcinoma after percutaneous ablation therapy

Objective: The aims of this study were to identify prognostic factors in patients who received a non‐surgical second treatment for the development of recurrent hepatocellular carcinoma (HCC) after an initial percutaneous ablation therapy. Methods: We retrospectively studied 147 patients with HCC who had received an initially successful percutaneous ablation therapy. The patients were followed up using computed tomography and/or ultrasound every 3 months and a second treatment was performed for subsequent recurrent tumours. Results: The 3‐ and 5‐year survival rates of the 147 patients were 90 and 65% respectively. During a mean follow‐up period of 33 months, local or distant tumour recurrences developed in 77 of the 147 patients, and the 3‐ and 5‐year survival rates after a second treatment in these 77 patients were 73 and 44% respectively. Forty‐six of the 77 patients with up to three recurrent tumours received percutaneous ablation therapy for the second treatment, and the remaining 31 patients with more than three (multiple) recurrent tumours received transcatheter arterial chemoembolization for their second treatment. A multivariate analysis revealed the serum α‐fetoprotein level at the time of the appearance of the recurrent HCC (<100 ng/ml vs ≥100 ng/ml, P=0.009) and the number of recurrent tumours (up to three vs more than three, P=0.009) to be independent prognostic factors after the second treatment. Conclusions: The serum α‐fetoprotein level and recurrent tumour number were prognostic factors following the second treatment in patients with recurrent HCC who had received an initially successful ablation therapy.     

Expression of galectin‐3 involved in prognosis of patients with hepatocellular carcinoma

Aims: Galectins are multifunctional lectins binding to the β‐galactoside of glycoproteins that affect diverse physiological and pathophysiological processes such as development, inflammation and tumor growth. In hepatocellular carcinoma (HCC), the over‐expression of galectin‐1, 3, and 4 has been reported, although their function and correlation with tumor progression remain unknown. Thus, we aimed to assess the role of galectin‐3 during HCC progression. Methods: Specimens were obtained during curative operations and used for immunohistochemical analysis of galectin‐3 (n = 52), and statistically assessed for correlations with the clinical profiles and the prognoses of the patients. The serum galectin‐3 levels from the patients with liver diseases including HCC were assessed by ELISA. Results: In total, galectin‐3 expression was found in 34 of 52 tumors (65%) and was statistically correlated with histological differentiation and vascular invasion. Kaplan‐Meier's analysis showed that patients with galectin‐3 expression tended to relapse in the earlier phase and had worse overall survival. In particular, a higher expression rate of nuclear galectin‐3 showed a markedly worse prognosis, and it was independent in the multivariate analysis for overall survival. Serum galectin‐3 levels were significantly increased in HCC compared with chronic liver disease. The sensitivity and specificity of galectin‐3 were equivalent to alpha‐fetoprotein and Vitamin K absence or antagonist II, and the combination of HCC biomarkers with galectin‐3 improved the diagnostic performance. Conclusions: Galectin‐3 expression was involved in the tumor progression and related to the prognosis of HCC. Our observations suggested that galectin‐3 could be a novel tumor marker and therapeutic target.     

肝细胞癌组织中信号素3F 蛋白表达变化及其与患者预后的关系

目的：探讨肝细胞癌（HCC）组织中信号素3F（SEMA3F）蛋白表达与患者预后的关系。方法采用Western blot法检测32例HCC患者手术切除的HCC组织（ HCC组）和相应癌旁肝组织（对照组）标本中的SEMA3F蛋白表达,分析SEMA3F蛋白表达水平与HCC临床病理特征、复发转移及预后的关系。结果 HCC组及对照组SEMA3F蛋白表达阳性率分别为84％、97％,HCC组SEMA3F蛋白表达量低于对照组（P＜0．05）。肿瘤有包膜者SEMA3F蛋白表达量高于无包膜者,肿瘤为单个结节者表达量高于多个结节者（P均＜0．05）。 HCC组有、无肝硬化者的SEMA3F蛋白表达量差异无统计学意义。15例SEMA3F蛋白低表达者复发率显著高于17例高表达者,生存时间短于高表达者（P均＜0．05）。结论 SEMA3F可能在抑制HCC的侵袭转移中起重要作用。癌组织中SE-MA3F表达水平有助于判断HCC患者的预后。     

Living donor liver transplantation in hepatocellular carcinoma beyond the Milan criteria

Background/Aims: In patients with hepatocellular carcinoma (HCC) exceeding the Milan criteria, the recurrence rate after liver transplantation is over 50%. We investigated pretransplant factor(s) that could predict recurrence after living donor liver transplantation (LDLT) in patients with HCC exceeding the Milan criteria. Methods: Pre‐operative imaging showed that, of the 111 HCC patients who underwent LDLT between June 1995 and January 2006, 37 exceeded the Milan criteria. Clinical factors before LDLT were evaluated. Results: The 1‐ and 3‐year cumulative recurrence rates were 35 and 55% respectively. Pretransplant risk factors for HCC recurrence were large tumour size (>6 cm, P=0.001), tumour exposed to the liver surface (P=0.014) and progressive disease after pretransplant treatment (P=0.038). The 2‐year HCC recurrence rates in patients with 0, 1, 2 and 3 factors were 0% (0/4), 9% (1/16), 80% (8/10) and 100% (7/7) respectively (P<0.001). The 2‐year survival rate was significantly higher in patients with 0 or 1 factor than in patients with two or more factors (P=0.022). Conclusions: In patients with HCC exceeding the Milan criteria, the three pretransplant factors that may be useful for identifying those with high HCC recurrence potential after LDLT are tumour size >6 cm, progressive disease after pretransplant treatment and tumour exposed to the liver surface.     

Analysis of factors affecting long-term survival of patients with hepatocellular carcinoma following hepatectomy

The survival of 200 patients (172 males, 28 females; mean age ± SD: 53.6 ± 12 years) who underwent hepatectomy for hepatocellular carcinoma (HCC) was analyzed retrospectively to identify prognostic determinants to guide patient selection for appropriate treatment. All patients studied had had complete macroscopic extirpation of their tumor, histologic information regarding their lesions and the adjacent non-tumorous liver parenchyma, and no evidence of residual or recurrent disease 30 days after surgery. Survival was analyzed with reference to 25 different clinical (n=7), serological (n=2), macroscopic (n=4), and histological (n=12) features of the resected specimens, by using multivariate analysis. Recurrent HCC was detected in 138 patients within a median follow-up period of 12.6 months. While 33 patients had extra-hepatic disease alone, in 74, the recurrence was confined to the hepatic remnant. Survival at 1, 3, and 5 years was 58%, 34%, and 26%, respectively. The presence of residual histologic disease at the resection margin was found to be the only important prognostic determinant (P < 0.02). The distance of the macroscopic resection margin, either at 1 or 2 cm, made no difference to the long-term outcome of our patients. Following hepatectomy, a detailed pathologic examination of the resected liver specimen is mandatory to verify the status of disease clearance, as the distance of the gross surgical margin is an unreliable index.     

人蛋白酶体β亚基4型在肝细胞癌中的表达及与预后的关系

目的 探讨人蛋白酶体β亚基4型(PSMB4)在肝细胞癌(以下简称肝癌)组织及正常肝组织中的表达及其在临床预后中的意义。方法 收集2017年1月-10月在南通大学附属医院行手术治疗的8例肝癌组织及癌旁组织标本,应用Western Blot法检测肝癌组织及相应癌旁组织中PSMB4蛋白的表达情况。另收集2009年1月-2012年10月南通大学附属医院留存的105例肝癌组织和25例正常肝组织的石蜡包埋标本,应用免疫组化法进一步检测PSMB4的表达情况。根据PSMB4免疫组化结果差异将105例肝癌患者分为PSMB4高表达组(n=57)和PSMB4低表达组(n=48)。计量资料2组间比较采用独立样本t检验;计数资料2组间比较采用χ2检验。Cox风险回归模型分析2组患者临床病理特征及预后的关系,Kaplan-Meier生存曲线分析不同PSMB4水平患者的生存情况。结果 2组间HBV感染、肿瘤最大直径、肿瘤分化程度、TNM分期比较差异均有统计学意义(χ^2值分别为22.482、8.219、14.964、6.587,P值均<0.05)。105例肝癌患者中57例(54.29%)为PSMB4 高表达,48例(45.71%)为PSMB4低表达;而25例正常肝组织中8例(32%)为PSMB4高表达,17例(68%)为PSMB4低表达或不表达,2组表达情况比较差异有统计学意义(χ^2=4.011, P<0.05)。PSMB4染色主要分布于细胞浆和细胞核内,染色呈棕色及棕黄色颗粒样。8例新鲜肝癌及癌旁组织样本中有7例肝癌组织的PSMB4蛋白表达水平明显高于癌旁组织(P值均<0.05)。单因素分析显示患者的5年生存状态与肿瘤大小(P=0.01)、转移情况(P<0.001)、分化程度(P=0.01)、TNM分期(P=0.003)以及PSMB4表达水平(P<0.001)有关;多因素结果显示肿瘤转移[风险比(HR)=11.375,95%可信区间(95%CI):4.911~26.348)]和PSMB4高表达(HR=6.834,95%CI: 2.939~15.889)是肝癌患者的独立危险因素(P值均<0.001)。PSMB4高表达组患者5年生存率明显低于PSMB4低表达组(27.6% vs 79.2%, χ^2=22.96,P<0.05)。结论 PSMB4在肝癌组织中的表达增高,并且其高表达是肝癌患者预后的独立危险因素,PSMB4有可能作为肝癌预后的潜在标志及治疗的潜在靶点。     

活体肝移植治疗原发性肝癌的价值与风险评价

目的评价活体肝移植治疗原发性肝癌的价值与风险。方法自2002年1月至2006年12月，四川大学华西医院肝脏移植中心对27例原发性肝癌患者实施活体肝移植治疗，其中25例接受右半肝移植物，2例接受双供体移植物；对这27例受体及其29例供体的临床资料和随访结果进行回顾性分析。结果本组供体无死亡发生，并发症发生率为17．24％（5例），其中2例（6．90％）发生较严重的并发症，包括腹腔内出血及门静脉栓塞各l例；3例（10．34％）并发症较轻，伤口脂肪液化并感染、胸腔积液及乳糜漏各l例；所有供体目前都已完全康复，并回到以前的工作岗位。本组受体无一例发生小肝综合征，全组病例1年及3年累积生存率分别为84．01％及71．40％，与同期因各种其他非恶性疾病进行的成人活体肝移植受体1年及3年累积生存率（83．30％及75．51％）比较，两者差异无统计学意义（P〉0．05）。结论虽然活体肝移植治疗原发性肝癌对供体的风险及受体的益处尚需进一步的研究评价，但研究结果已初步表明，只要我们努力作好每一个细节，活体肝移植对供体来说是一相对安全的手术；而对肝癌患者来说则能相对满意地延长生存期，值得进一步推广运用。     

Evaluating the predictive power of circulating tumor cells for the prognosis of transarterial chemoembolization treatment on patients with advanced hepatocellular carcinoma

Explore the predictive power of Circulating Tumor Cells (CTCs) for evaluating the prognosis of transarterial chemoembolization (TACE) treatment on advanced hepatocellular carcinoma (HCC) patients, and use it to construct a prediction model.We retrospectively analyzed 43 patients with Barcelona Clinic Liver Cancer stage C HCC who underwent TACE treatment.The survival time of 43 advanced HCC patients were 2 to 60 months, with the median survival time of 12 months, 1-, 3-, and 5-year survival rates were 42.9%, 9.0%, and 3.6%, respectively. The OS of patients with high level of CTCs before TACE (CTC1 > 2) was significantly lower than that of patients with low level of CTCs (8 vs 12 months, P = .040), but there was no significant difference in PFS between the 2 groups (P = .926). Meanwhile, there was no significant difference in OS and PFS between patients with high level CTCs and those with low level CTCs at 1 week and 4 weeks after TACE (P all > .05). In univariate and multivariate Cox regression analysis, the number of lesions and CTC before TACE were the independent influencing factors for prognosis in these patients, and the HR was 3.01 and 1.20, respectively (all P < .05). The area under curve of COX regression model to predict OS increased with the increase of follow-up time, ranging from 0.56 to 0.85.The CTCs number before TACE is an effective biomarker for predicting the OS of advanced HCC patients. The joint prediction model based on CTCs and tumor number can effectively predict the prognosis of patients with advanced HCC.