Dual energy computed tomography for detection of metastatic lymph nodes in patients with hepatocellular carcinoma

BACKGROUND Regional lymph node metastasis in patients with hepatocellular carcinoma(HCC)is not uncommon, and is often under-or misdiagnosed. Regional lymph node metastasis is associated with a negative prognosis in patients with HCC, and surgical resection of lymph node metastasis is considered feasible and efficacious in improving the survival and prognosis. It is critical to characterize lymph node preoperatively. There is currently no consensus regarding the optimal method for the assessment of regional lymph nodes in patients with HCC.AIM To evaluate the diagnostic value of single source dual energy computed tomography(CT) in regional lymph node assessment for HCC patients.METHODS Forty-three patients with pathologically confirmed HCC who underwent partial hepatectomy with lymphadenectomy were retrospectively enrolled. All patients underwent dual-energy CT preoperatively. Regional lymph nodes(n = 156) were divided into either a metastatic(group P, n = 52) or a non-metastasis group(group N, n = 104), and further, according to pathology, divided into an active hepatitis(group P1, n = 34; group N1, n = 73) and a non-active hepatitis group(group P2, n = 18; group N2, n = 31). The maximal short axis diameter(MSAD),iodine concentration(IC), normalized IC(NIC), and the slope of the spectralcurve(λ_HU) of each group in the arterial phase(AP), portal phase(PP), and delayed phase(DP) were analyzed.RESULTS Analysis of the MSAD, IC, NIC, and λ_HU showed statistical differences between groups P and N(P < 0.05) during all three phases. To distinguish benign from metastatic lymph nodes, the diagnostic efficacy of IC, NIC, and λ_HU in the PP was the best among the three phases(AP, PP, and DP), with a sensitivity up to 81.9%,83.9%, and 81.8%, and a specificity up to 82.4%, 84.1% and 84.1%, respectively.The diagnostic value of combined analyses of MSAD with IC, NIC, or λ_HU in the PP was superior to the dual energy CT parameters alone, with a sensitivity up to84.5%, 86.9%, and 86.2%, and a specificity up to 83.0%, 93.6% and 89.8%,respectively. Between groups P1 and P2 and groups N1 and N2, only IC, NIC,and λ_HU between groups N1 and N2 in the PP had a statistically significant difference(P < 0.05).CONCLUSION Dual-energy CT contributes beneficially to regional lymph node assessment in HCC patients. Combination of MSAD with IC, NIC, or λ_HU values in the PP is superior to using any single parameter alone. Active hepatitis does not deteriorate the capabilities for characterization of metastatic lymph nodes.     

Staging systems for hepatocellular carcinoma: Current status and future perspectives

Hepatocellular carcinoma(HCC) is a major health concern worldwide and the third cause of cancer-related death. Despite advances in treatment as well as careful surveillance programs, the mortality rates in most countries are very high. In contrast to other cancers, the prognosis and treatment of HCC depend on the tumor burden in addition to patient’s underlying liver disease and liver functional reserve. Moreover, thereis considerable geographic and institutional variation in both risk factors attributable to the underlying liver diseases and the management of HCC. Therefore, although many staging and/or scoring systems have been proposed, there is currently no globally accepted system for HCC due to the extreme heterogeneity of the disease. The aim of this review is to focus on currently available staging systems as well as those newly reported in the literatures since 2012. Moreover, we describe problems with currently available staging systems and attempts to modify and/or add variables to existing staging systems.     

Inhibitory effect of the angiogenesis inhibitor TNP-470 on tumor growth and metastasis in nude mice bearing human hepatocellular carcinoma

The antitumor and anti-metastatic effects of a potent angiogenesis inhibitor,O-(chloroacetyl-carbamoyl)fumagillol (TNP-470), was investigated in a highly metastatic model of human hepatocellular carcinoma—LCI-D20. Small pieces of LCI-D20 tumor tissue were implanted subcutaneously into the right axillary region of 24 nude mice; the mice were then randomized into two groups. To one group, TNP-470 30 mg/kg was given as a subcutaneous injection every other day from day 1 to day 15 and the mice were sacrificed on day 26. An antitumor effect of TNP-470 was clearly demonstrated by tumor weight (0.97±0.34 g compared to 2.04±0.34 g,P<0.001) and -Fetoprotein value (93±59 g/L compared to 769±282 g/L,P<0.001). There was also an anti-metastatic effect of TNP-470. Lung metastases developed in only 1 of 12 mice in the treated group, while they developed in 6 of mice of the control group. No severe side-effect of TNP-470 was found in this study. In vitro study revealed that the purified hepatoma cells were insensitive to TNP-470 (the 50% inhibitory concentration was 43 g/ml). These results suggest that the angiogenesis inhibitor TNP-470 has both strong antitumor and anti-metastatic effects on a human hepatocellular carcinoma model in nude mice.Abbreviations TNP-470 O-(chloroacetyl-carbamoyl) Fumagillol - MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide This work was partly supported by the CHina Medical Board of New York, grant 93-583, and a Leading Speciality grant of Shanghai Health Bureau     

Validation of modified albumin-bilirubin-TNM score as a prognostic model to evaluate patients with hepatocellular carcinoma

BACKGROUND An ideal staging system for hepatocellular carcinoma(HCC) should rely on the hepatic reserve function and tumor burden. With the improvement in diagnostic and treatment strategies for HCC, in addition to recent treatment of viral hepatitis, finding a suitable assessment tool for hepatic reserve has become mandatory.AIM To validate a recently proposed modified albumin-bilirubin-TNM(mALBI-T)grade as a prognostic model for patients with HCC in Egypt.METHODS For patients diagnosed with HCC, Child-Turcotte-Pugh(CTP) score, Barcelona Clinic Liver Cancer(BCLC) stage, albumin-bilirubin(ALBI), plateltetalbumin–bilirubin(PALBI), ALBI-based BCLC, ALBI-T and mALBI-T grades were estimated. Patients were followed from time of diagnosis to date of death or date of data collection if they remained alive. Overall survival and received treatments were determined. Survival data were analyzed.RESULTS A total of 1910 patients were included(mean age, 57 years; 1575 males). At presentation, 50.6% had CTP A, 36.1% had CTP B and 13.4 % had CTP C; 12%had ALBI grade 1, 62.3% had ALBI grade 2 and 24.7% had ALBI grade 3. Overall median survival was 13 mo; survival was better in patients with ALBI 1 than in those with ALBI 2 and 3(28.6 vs 14 and 5.8 mo, respectively, P 0.001). Patients with ALBI-T grades 0 and 1 had better survival than those with ALBI-T grades 2,3, 4 and 5(P 0.001). The modified ALBI-T showed better stratification and significant improvement in prediction of survival.CONCLUSION ALBI-T grade is a superior prognostic tool that selects patients with HCC who have better liver reservoir and tumor stage. mALBI-T is a better prognostic model in patients with HCC.     

Metastatic recurrence to a solitary lymph node four years after hepatic lobectomy for primary hepatocellular carcinoma

This report describes a patient that developed recurrent metastatic hepatocellular carcinoma (HCC) to a suprapancreatic lymph node four years after being treated for primary HCC via complete left hepatectomy. Metastatic HCC was proven by pathologic confirmation. The report addresses the role of surgical resection as a treatment modality for recurrent HCC to solitary lymph nodes. The role of biological chemotherapy as adjuvant treatment is also addressed.     

Survivin-positive circulating tumor cells as a marker for metastasis of hepatocellular carcinoma

BACKGROUNDCirculating tumor cells (CTCs) and survivin are indicators for tumor stage and metastasis, as well as epitheliomesenchymal transition, in various cancers, including hepatocellular cancer (HCC). AIMTo explore the potential of survivin-positive CTCs, specifically, as a marker for tumor progression in HCC patients.METHODSWe examined the survivin expression pattern in CTCs obtained from 179 HCC patients, and investigated the in vitro effects of survivin silencing and overexpression on the proliferation and invasion of HCC cells. CTC count and survivin expression in patient samples were examined using RNA in situ hybridization.RESULTSAll 179 patients were positive for CTC markers, and 94.41% of the CTCs were positive for survivin. The CTC and survivin-positive CTC counts were significantly higher in the HCC patients than in the normal controls, and were significantly associated with tumor stage and degree of differentiation. Further, survivin overexpression was found to induce HepG2 cell proliferation, reduce apoptosis, and improve invasive ability.CONCLUSIONSurvivin shows upregulated expression (indicative of anti-apoptotic effects) in HCC. Thus, survivin-positive CTCs are promising as a predictor of HCC prognosis and metastasis, and their accurate measurement may be useful for the management of this cancer.     

肝细胞癌在血中微小转移的检测

目的 肝细胞癌患者术后复发常是术前不能检出微转移灶或术中癌细胞释放入血之故。建立早期检出肝细胞癌（HCC）血中微小转移的方法并评价其临床意义。方法 采用巢式RT－PCR检测肝细胞特异白蛋白（ALB）mRNA和甲胎蛋白（AFP）mRNA在HCC患者外周血有核细胞成分及组织标本中的表达情况。并以肝癌细胞系HepG2、SMMC7721,乳腺癌细胞MCF－7作为阳性，阴性对照。结果 在肝组织，无论是癌、癌旁还是正常组织，ALB mRNA的表达均为阳性（8／8），而AFP mRNA在癌组织7／8例表达，癌旁5／8例表达。外周血表达的情况为：同一组标本ALB mRNA的阳性率为75.6%（34／45，P＜0．01），AFPmRNA的阳性率为57．8％（26／45，P＜0．01）。在有肝外转移和无肝转移分组中，ALBmRNA和AFPmRNA的表达分别为100．0％，54．2％和29．2％。结论 在HCC患者外周血有核心细胞成分中检测ALBmRNA和AFPmRNA的表达，是预测转移、复发的简捷手段，若ALB与AFP二者联合使用，应用性会更强。     

A proposal of the modified liver damage classification for hepatocellular carcinoma.

OBJECTIVE: The purpose of this study was to evaluate the validity of the two common classifications for assessing liver function; the Child-Pugh classification and the liver damage classification. We also examined the feasibility of the modified liver damage classification. METHODS: A total of 2306 HCC patients diagnosed between 1990 and 2002 were categorized according to the three classifications. The modified liver damage classification is calculated by summation of the scores for five variables (serum bilirubin level, serum albumin level, prothrombin activity, ICG retention rate at 15min, ascites) of the liver damage classification and classified patients into grades A-C in the similar manner as the Child-Pugh classification. The differences in distribution and survival rate of the patients in each group were compared. RESULTS: With respect to the patient distribution, 1787 (77.5%) and 469 (20.3%) patients were categorized into Child-Pugh grades A and B, respectively, whereas 1187 (51.5%) and 962 (41.7%) patients were categorized into liver damage grades A and B, respectively. As a result of this disproportionate distribution, survival rates of Child-Pugh grades A and B were lower than those of the liver damage grades A and B. Furthermore, some discrepancies were found in the distribution of patients between the liver damage classification and the modified liver damage classification. One hundred and forty-one patients of the 1187 liver damage grade A patients were categorized into grade B by the modified liver damage classification and 71 patients of the 962 liver damage grade B patients were categorized into grade C by the modified liver damage classification. The survival rates of these subgroups were similar to those of the liver damage grades B and C, respectively. CONCLUSION: The modified liver damage classification appears to be the best available tool for assessing residual liver function, for estimating the survival of Japanese HCC patients and for making decisions concerning the treatment of these patients.     

Predictive value of gross classification of hepatocellular carcinoma on recurrence and survival after hepatectomy

BACKGROUND/AIM: A new gross classification of hepatocellular carcinoma in which Eggel's nodular type is subclassified into type 1 (single nodular type), type 2 (single nodular type with extranodular growth), and type 3 (contiguous multinodular type) has been widely used in Japan. The aim of the study was to determine whether this classification is correlated with patient outcome. METHODS: Sixty-five resected hepatocellular carcinoma nodules (< or = 5 cm) were classified using this new classification. RESULTS: The 65 tumors were classified into 30 type 1 (46%), 20 type 2 (31%), and 15 type 3 (23%) hepatocellular carcinomas. The rate of microscopic vascular invasion significantly increased from type 1 to type 2, and to type 3 tumors (p=0.03). Kaplan-Meier estimates showed that type 1 was significantly associated with lower recurrence rate (type 1 vs. type 2, p=0.01; type 1 vs. type 3, p=0.004; log-rank test), and higher disease-specific survival (type 1 vs. type 2, p=0.02; type 1 vs. type 3, p=0.002). Cox's proportional-hazards model demonstrated that type 1 was an independent factor for low risk of recurrence (p=0.002) and low risk of disease-specific death (p=0.02). CONCLUSION: The gross classification of hepatocellular carcinoma is of clinical value in predicting patient outcome.     

类胰岛素生长因子与肝癌

肝癌是常见的恶性肿瘤之一,其病程快且预后很差.其发生是一个多因素多步骤协同的复杂过程.近来的研究报道,肝癌发生分子机制与类胰岛素生长因子体系信号通路异常相关,类胰岛素生长因子是一种多功能细胞增殖调控因子,他在胚胎发育、中枢神经系统发育及肿瘤细胞增殖等方面具有重要的生物学功能.类胰岛素生长因子的生物学活性受到包括类胰岛素...     

Inflammation scores predict survival for hepatitis B virus-related hepatocellular carcinoma patients after transarterial chemoembolization

AIM:To compare the prognostic ability of inflammation scores for patients with hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC)undergoing transarterial chemoembolization(TACE).METHODS:Data of 224 consecutive patients who underwent TACE for unresectable HBV-related HCC from September 2009 to November 2011 were retrieved from a prospective database.The association of inflammation scores with clinicopathologic variables and overall survival(OS)were analyzed,and receiver operating characteristic curves were generated,and the area under the curve(AUC)was calculated to evaluate the discriminatory ability of each inflammation score and staging system,including tumor-node-metastasis,Barcelona Clinic Liver Cancer,and Cancer of the Liver Italian Program(CLIP)scores.RESULTS:The median follow-up period was 390 d,the one-,two-,and three-year OS were 38.4%,18.3%,and 11.1%,respectively,and the median OS was 390d.The Glasgow Prognostic Score(GPS),modifed GPS,neutrophil-lymphocyte ratio,and Prognostic Index were associated with OS.The GPS consistently had a higher AUC value at 6 mo(0.702),12 mo(0.676),and24 mo(0.687)in comparison with other inflammation scores.CLIP consistently had a higher AUC value at6 mo(0.656),12 mo(0.711),and 24 mo(0.721)in comparison with tumor-node-metastasis and Barcelona Clinic Liver Cancer staging systems.Multivariate analysis revealed that alanine aminotransferase,GPS,and CLIP were independent prognostic factors for OS.The combination of GPS and CLIP(AUC=0.777)was superior to CLIP or GPS alone in prognostic ability for OS.CONCLUSION:The prognostic ability of GPS is superior to other inflammation scores for HCC patients undergoing TACE.Combining GPS and CLIP improved the prognostic power for OS.     

The prognostic significance of preoperative plasma levels of osteopontin in patients with hepatocellular carcinoma

We aimed to evaluate the prognostic value of preoperative plasma osteopontin (OPN) levels in 101 patients with hepatocellular carcinoma (HCC) who underwent liver resection. Plasma OPN levels were detected by ELISA. The association of plasma OPN levels of patients with clinicopathological characteristics, tumor recurrence, and survival was analyzed. The median plasma OPN level of patients was 176.90 ng/ml (range 13.73–780.00 ng/ml), which was significantly higher than that of 24 healthy volunteers (63.74 ng/ml, range 12.20–122.32 ng/ml). Plasma OPN levels were significantly different in patients with different numbers of tumor nodules (168.18 and 217.11 ng/ml for single and multiple nodules, respectively; P = 0.002), different Edmondson’s grades (201.24, 168.36, and 503.58 ng/ml for grades I, II, and III/IV, respectively; P = 0.015), and different TNM stages (168.16, 167.54, and 216.18 ng/ml for stages I, II, and III/IV, respectively; P = 0.016). Significantly higher plasma OPN levels were found in patients with a recurrence of HCC after resection, compared with those without recurrence (213.55 versus 153.70 ng/ml; P = 0.0013). A higher plasma OPN level was a leading independent prognostic factor for both overall survival (OS) and disease-free survival (DFS) in univariate and multivariate Cox models. This suggests that the preoperative plasma OPN level can be used as a predictive marker for HCC recurrence and may be helpful to assess the prognosis of patients with HCC after surgery.     

肝细胞癌四种临床分期系统预后判断和治疗指导价值的比较

目的 比较4个分期系统[巴塞罗那临床肝癌分期标准(BCLC)、日本综合分期积分(JIS)、意大利肝癌评分(CLIP)和国内分期]对中国肝癌患者预后判断和对治疗方案选择的指导意义.方法 回顾性分析2001年至2002年复旦大学附属中山医院收治的861例初发肝细胞癌患者的临床资料,分别按4个分期系统分期或评分,比较各期患者的生存情况以及不同治疗方案对其生存的影响.结果 在判断预后方面,BCLC、JIS和国内分期系统的各分期间生存率差异均有统计学意义;而在CLIP分期的一些评分间的生存率差异无统计学意义.在指导治疗方面,BCLC C期,CLIP 3、4分以及国内分期ⅢA期的患者接受手术治疗与接受肝动脉化学治疗栓塞(TACE)和(或)肝动脉栓塞(TAE)治疗的生存率差异无统计学意义;而比这些更早期的患者接受手术治疗的生存率优于接受TACE和(或)TAE治疗的生存率.结论 BCLC、JIS和国内分期系统在判断预后方面适用于中国患者;但仅国内分期和BCLC分期同时兼备了判断预后和指导治疗两方面的作用.     

Safety of hepatectomy for elderly patients with hepatocellular carcinoma

The number of elderly patients with hepatocellular carcinoma (HCC) has been increasing. Characteristics of elderly HCC patients are a higher proportion of females, a lower rate of positive hepatitis B surface antigen, and a higher rate of positive hepatitis C antibodies. Careful patient selection is vital for performing hepatectomy safely in elderly HCC patients. Treatment strategy should be decided by not only considering tumor stage and hepatic functional reserve, but also physiological status, including comorbid disease. Various assessment tools have been applied to predict the risk of hepatectomy. The reported mortality and morbidity rates after hepatectomy in elderly HCC patients ranged from 0% to 42.9% and from 9% to 51%, respectively. Overall survival rate after hepatectomy in elderly HCC patients at 5 years ranged from 26% to 75.9%. Both short-term and long-term results after hepatectomy for strictly selected elderly HCC patients are almost the same as those for younger patients. However, considering physiological characteristics and the high prevalence of comorbid disease in elderly patients, it is important to assess patients more meticulously and to select them strictly if scheduled to undergo major hepatectomy.     

Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma

Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.     

碱性成纤维细胞生长因子在肝细胞癌中的表达及意义

目的 探讨bFGF在肝细胞癌中的表达及其临床病理意义。方法 使用免疫组化SABC法检测41例肝细胞癌手术切除标本及5例外伤性肝破裂肝切取标本。结果 正常对照组bFGF均为阴性。肝细胞癌组bFGF阳性率为70．7％（29／41）。bFGF表达与患者年龄、性别、AFP是否阳性、HBsAg是否阳性无关（P＞0．05）；而与肝癌分化程度、有无癌栓、包膜是否完整有关。在高侵袭转移组与低侵袭转移组间，bFGF阳性率分别为86．4％和52．6％，差异具有显著性（P＜0．05）。结论 bFGF在肝细胞癌中高表达，可以作为判断肝癌恶性程度及转移潜能的参考指标。     

Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma

ABM: Recent studies suggested that cyclooxygenase-2 (COX-2) enhances tumor angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Although COX-2 expression has been demonstrated in hepatocellular carcinoma (HCC), the significance of COX-2 in progression of HCC remains unclear. This study evaluated the clinico-pathological correlation of COX-2 level and its relationship with VEGF level in HCC. METHODS: Fresh tumor tissues were obtained from 100 patients who underwent resection of HCC. COX-2 protein expression was examined by immunohistochemistry, and quantitatively by an enzyme immunometric assay (EIA) of tumor cytosolic COX-2 levels. Tumor cytosolic VEGF levels were measured by an ELISA. RESULTS: Immunostaining showed expression of COX-2 in tumor cells. Tumor cytosolic COX-2 levels correlated with VEGF levels (r = 0.469,P<0.001). Correlation with clinicopathological features showed significantly higher tumor cytosolic COX-2 levels in the presence of multiple tumors (P = 0.027), venous invasion (P = 0.030), microsatellite lesions (P=0.037) and advanced tumor stage (P = 0.008). Higher tumor cytosolic COX-2 levels were associated with worse patient survival. CONCLUSION: This study shows that elevated tumor COX-2 levels correlate with elevated VEGF levels and invasiveness in HCC, suggesting that COX-2 plays a significant role in the progression of HCC.