肝细胞癌肝移植术后免疫抑制剂的应用

肝移植已经成为肝细胞癌根治性治疗的重要手段,但术后复发与转移严重限制了肝细胞癌肝移植的疗效。近年来,国内外学者围绕肝移植术后免疫抑制剂的应用与肝细胞癌复发转移的关系进行了一系列研究。现就肝细胞癌肝移植术后免疫抑制剂的临床应用策略及建议作一简述,以更好地指导临床。     

The prognostic significance of clinical and pathological features in hepatocellular carcinoma

The prognosis of patients with HCC still remains dismal. The life expectancy of HCC patients is hard to predict because of the high possibility of postoperative recurrence. Many factors, such as patient's general conditions, macroscopic tumor morphology, as well as tumor histopathology features, have been proven of prognostic significance. Female HCC patient often has a better prognosis than male patient, which might be due to the receptor of sex hormones. Younger patients often have tumors with higher invasiveness and metastatic potentials, and their survival and prognosis are worse than the older ones. Co-existing hepatitis status and hepatic functional reserve have been confirmed as risk factors for recurrence. Serum alpha-fetoprotein (AFP) is useful not only for diagnosis, but also as a prognostic indicator for HCC patients. AFP mRNA has been proposed as a predictive marker of HCC cells disseminated into the circulation and for metastatic recurrence. Many pathologic features, such as tumor size, number, capsule state, cell differentiation, venous invasion, intrahepatic spreading, and advanced pTNM stage, are the best-established risk factors for recurrence and important aspects affecting the prognosis of patients with HCC. Marked inflammatory cell infiltration in the tumor could predict a better prognosis. Clinical stage is still the most important factor influencing on the prognosis. Extratumor spreading and lymph nodal metastasis are independent predictors for poor outcome. Some new predictive systems have recently been proposed. Different strategies of treatment might have significant different effects on the patients' prognosis. To date, surgical resection is still the only potentially curative treatment for HCC, including localized postoperative recurrences. Extent of resection, blood transfusion, occlusion of porta hepatis, and blood loss affect the survival and prognosis of HCC patients. Regional therapies provide alternative ways to improve the prognosis of HCC patients who have no opportunity to receive surgical treatment or postoperative recurrence. The combination of these treatment modalities is hopeful to further improve the prognosis. The efficacies of neoadjuvant (preoperative) or adjuvant (postoperative) chemotherapy or chemoembolization in preventing recurrence and on the HCC prognosis still remain great controversy, and deserve further evaluation. Biotherapy, including IFN-alpha therapy, will play more important role in preventing recurrence and metastasis of HCC after operation.     

Portal venous invasion: the single most independent risk factor for immediate postoperative recurrence of hepatocellular carcinoma

Background and Aim: Despite improvements of treatment in hepatocellular carcinoma (HCC), the recurrence rate after curative hepatic resection still remains remarkably high. An immediate recurrence of HCC after surgery is frustrating. We tried to clarify risks of immediate postoperative recurrence of HCC; that is, within 4 months after curative hepatic resection. Methods: A total of 167 patients with HCC underwent hepatic resection; 60 had immediate postoperative recurrences (IPR group), and 107 had disease‐free survival for more than 5 years (DFS group). Variables were compared between the two groups. Results: Univariate analysis showed the following variables were significant risk factors for immediate postoperative recurrence of HCC: male sex, elevated serum aspartate aminotransferase level, greater amount of blood loss, longer operation time, worse tumor differentiation, higher tumor node metastasis stage, and presence of any of the following: intrahepatic metastasis, tumor‐rupture, portal venous invasion, or microvascular invasion. In multivariate analysis, only portal venous invasion was a significant risk factor (odds ratio = 3.2, P = 0.03, standard error = 0.5, Logistic regression analysis). Conclusions: Portal venous invasion may be the most significant risk factor for immediate postoperative recurrence of HCC. However, accurate assessment of this risk factor may require histological examination, limiting its utility as a preoperative predictor. Further research is necessary to definitively identify preoperative predictors.     

Clinical analysis of the risk factors for recurrence of HCC and its relationship with HBV

AIM: To comprehend the risk factors of recurrence of hepatocellular carcinoma (HCC) and its relationship with the infection patterns of hepatitis B virus (HBV).METHODS: All materials of 270 cases of postoperative HCC were statistically analyzed by SPSS software.Recurrence and metastasis were classified into early( ≤2 years) and late phase (>2 years). Risk factors for recurrence and metastasis after surgery in each group were analyzed.RESULTS: Out of 270 cases of HCC, 162 cases were followed up in which recurrence and metastasis occurred in 136 cases. There were a lot of risk factors related to recurrence and metastasis of HCC; risk factors contributing to early phase recurrence were serum AFP level, vascular invasion, incisal margin and operative transfusion, gross tumor classification and number of intrahepatic node to late phase recurrence. The HBV infective rate of recurrent HCC was 94.1%, in which ““HBsAg, HBeAb, HBcAb““ positive pattern reached 45.6%. The proportion of HBV infection in solitary large hepatocellular carcinoma (SLHCC)evidently decreased compared to nodular hepatocellular carcinoma (NHCC) (P<0.05).CONCLUSION: The early and late recurrence and metastasis after hepatectomy of HCC were associated with different risk factors. The early recurrence may be mediated by vascular invasion and remnant lesion, the late recurrence by tumor‘s clinical pathology propert, as multicentric carcinogenesis or intrahepatic carcinoma de novo. HBV replication takes a great role in this process.From this study, we found that SLHCC has more satisfactory neoplasm biological behavior than NHCC.     

Importance of achieving complete necrosis during the first treatment for hepatocellular carcinoma to prevent bone metastasis: a prospective study

BACKGROUND AND AIMS: Recent advances in the treatment of hepatocellular carcinoma (HCC) have changed the importance of bone metastasis during the follow up of such patients. In the present study, we investigated risk factors for bone metastasis after treatment for HCC. METHODS: Two hundred and two patients with HCC were diagnosed as free of bone metastasis by technecium 99m-methylene diphosphonate bone scintigraphy and were followed prospectively after treatment of the primary lesions (follow-up period 2-146 months; median 20 months). We statistically analyzed the risk factors for bone metastasis using the clinical characteristics at the time of first treatment. RESULTS: Multiple tumors (P < 0.005), main tumor size > 5 cm in diameter (P < 0.005), the presence of distant metastasis (P < 0.005), elevation of serum alpha-fetoprotein (> 100 ng/mL; P < 0.05), chemotherapy (P < 0.05) and insufficient therapeutic response (P < 0.0005) were identified as risk factors for bone metastasis by univariate analyses. Insufficient therapeutic response and main tumor size > 5 cm in diameter (both P < 0.05) were identified as independent predisposing factors for bone metastasis. CONCLUSIONS: Complete necrosis of primary HCC during the first treatment is important to prevent subsequent bone metastasis.     

Expression of X-linked inhibitor-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Despite significantly improved diagnosis and treatment in recent years, the long-term therapeutic effect is compromised by the frequent recurrence and metastasis, of which the molecular mechanisms are not fully understood. Our initial studies in established HCC cell lines with different metastatic capabilities indicated a correlation of metastasis with the resistance to apoptosis and therefore the ability to survive in stressed conditions. Subsequent investigation revealed that increased expression of X-linked inhibitor-of-apoptosis protein (XIAP) was correlated with the resistance to apoptosis and enhanced invasiveness in vitro, which could contribute to increased metastatic foci in vivo. Furthermore, we found that nearly 90% of clinical samples from advanced HCC patients expressed high levels of XIAP. Patients with XIAP-positive tumors had a significantly increased risk of relapse, which resulted from metastasis after total liver resection and orthotopic liver transplantation. Indeed, XIAP expression could be an independent prognostic factor for predicting disease-free survival rate and overall survival rate of these patients. XIAP expression was also highly correlated with advanced cases that exceeded the Milan criteria and could be a prognostic factor for disease-free survival in these patients as well. CONCLUSION: Our studies have shown an important molecule in controlling HCC metastasis, defined a biomarker that can be used to predict HCC recurrence and patient survival after treatment, and suggest that XIAP can be a molecular target subject to intervention to reduce metastasis and recurrence.     

根治性肝切除联合索拉非尼治疗肝细胞癌的研究进展

根治性肝切除仍然是肝细胞癌(hepatocellularcarcinoma,HCC)的主要治疗手段,但术后转移复发导致肝切除的疗效进入瓶颈期.探索术后复发的治疗措施是有效延长患者生存时间的重要课题.目前,以经皮肝动脉化疗栓塞为代表的多种治疗措施已在临床广泛开展,但尚缺乏大规模、多中心随机对照临床试验的循证医学证据.分子靶向药物索拉非尼的出现为改善HCC预后开辟了新局面,对于已接受过根治性肝切除治疗的HCC患者,索拉非尼可能是一种有效的辅助治疗方法,值得深入探索.     

Predictive factors affecting early recurrence after hepatectomy for hepatocellular carcinoma in 5-year survivors

BACKGROUND/AIMS: This study was undertaken to establish a therapeutic strategy for long-term recurrence-free survival in hepatocellular carcinoma (HCC) patients treated by hepatectomy by determining the factors that predict intrahepatic recurrence. METHODOLOGY: This study included 72 patients who survived more than 5 years after hepatectomy for HCC. Based on the interval between hepatectomy and intrahepatic recurrence, they were classified into 3 groups: those with early recurrence within 2 years after surgery (n=15), those with recurrence between 2 and 5 years (n=18), and those without recurrence within 5 years (n=39). Twenty-six parameters concerning host-related, tumor-related, treatment-related factors, and postoperative levels of serum transaminases were evaluated. RESULTS: Among host-related and tumor-related factors, serum albumin level, serum levels of transaminases, indocyanine green retention rate at 15 minutes, tumor number, intrahepatic metastasis and TNM stage were determined to be significantly different between the patients with recurrence within 5 years and those without recurrence. Among treatment-related factors, curability was highly associated with recurrence. The period until increase in the levels of transaminases after surgery was significantly shorter in patients with recurrence compared to the patients without recurrence. CONCLUSIONS: Curative operation minimizing intrahepatic metastasis and postoperative anti-inflammatory treatment lowering the occurrence of multicentric carcinogenesis are useful therapeutic strategies for achieving long-term recurrence-free survival for HCC patients treated with surgery.     

循环肿瘤细胞研究进展

循环肿瘤细胞(circulating tumor cells,CTCs)是指自发或因诊疗操作由实体瘤或转移灶释放进入外周血循环的肿瘤细胞,是恶性肿瘤患者出现术后复发和远处转移的重要原因.近年来,随着检测技术的不断改进,CTCs检测作为一种新型的非侵入性诊断工具,在早期发现患者术后复发与远处转移、评估疗效与预后等方面的应用价值已成为临床研究的热点.本文简要综述近年CTCs检测的研究进展及其临床应用状况.     

Sorafenib suppresses postsurgical recurrence and metastasis of hepatocellular carcinoma in an orthotopic mouse model

Surgical resection is the first-line treatment for hepatocellular carcinoma (HCC) patients with well-preserved liver function. Nevertheless, the rate of postoperative recurrence at 5 years is as high as 70%, and this gravely jeopardizes the therapeutic outcome. Clearly, new approaches are needed for preventing the relapse of this deadly disease. Taking advantage of a luciferase-labeled orthotopic xenograft model of HCC, we examined the role of sorafenib, the first systemic drug approved for advanced HCC patients, in the prevention of HCC recurrence. We found that sorafenib suppressed the development of postsurgical intrahepatic recurrence and abdominal metastasis and consequently led to prolonged postoperative survival of mice in this model. Furthermore, hyperactivity of extracellular signal-regulated kinase signaling caused by elevated levels of growth factors associated with postoperative liver regeneration enhanced the sensitivity of HCC cells to sorafenib; this provides a plausible explanation for the observation that recurrent tumors are more responsive to growth inhibition by sorafenib. CONCLUSION: Our results strongly suggest that by effectively reducing postoperative recurrence, sorafenib has a potential application in early-stage HCC patients who have undergone hepatectomy with curative intention.     

Prognostic and predictive blood biomarkers in gastric cancer and the potential application of circulating tumor cells

Gastric cancer(GC), with its high incidence and mortality rates, is a highly fatal cancer that is common in East Asia particularly in China. Its recurrence and metastasis are the main causes of its poor prognosis. Circulating tumor cells(CTCs) or other blood biomarkers that are released into the circulating blood stream by tumors are thought to play a crucial role in the recurrence and metastasis of gastric cancer. Therefore, the detection of CTCs and other blood biomarkers has an important clinical significance; in fact, they can help predict the prognosis, assess the staging, monitor the therapeutic effects and determine the drug susceptibility. Recent research has identified many blood biomarkers in GC, such as various serum proteins, autoantibodies against tumor associated antigens, and cell-free DNAs. The analysis of CTCs and circulating cell-free tumor DNA(ctDNA) in the peripheral blood of patients with gastric cancer is called as liquid biopsy. These blood biomarkers provide the disease status for individuals and have clinical meaning. In this review, we focus on the recent scientific advances regarding CTCs and other blood biomarkers, and discuss their origins and clinical meaning.     

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.     

Supportive therapies for prevention of hepatocellular carcinoma recurrence and preservation of liver function

Hepatocellular carcinoma(HCC) is one of the deadliest cancers in the world and is associated with a high risk of recurrence. The development of a wide range of new therapies is therefore essential. In this study, from the perspective of supportive therapy for the prevention of HCC recurrence and preservation of liver function in HCC patients, we surveyed a variety of different therapeutic agents. We show that branched chain amino acids(BCAA) supplementation and late evening snack with BCAA, strategies that address issues of protein-energy malnutrition, are important for liver cirrhotic patients with HCC. For chemoprevention of HCC recurrence, we show that viral control after radical treatment is important. We also reviewed the therapeutic potential of antiviral drugs, sorafenib, peretinoin, iron chelators. Sorafenib is a kinase inhibitor and a standard therapy in the treatment of advanced HCC. Peretinoin is a vitamin A-like molecule that targets the retinoid nuclear receptor to induce apoptosis and inhibit tumor growth in HCC cells. Iron chelators, such as deferoxamine and deferasirox, act to prevent cancer cell growth. These chelators may have potential as combination therapies in conjunction with peretinoin. Finally, we review the potential inhibitory effect of bone marrow cells on hepatocarcinogenesis.     

Predictors of early and late hepatocellular carcinoma recurrence

Hepatocellular carcinoma(HCC) is the most frequent liver neoplasm, and its incidence rates are constantly increasing. Despite the availability of potentially curative treatments(liver transplantation, surgical resection, thermal ablation), long-term outcomes are affected by a high recurrence rate(up to 70% of cases 5 years after treatment). HCC recurrence within 2 years of treatment is defined as “early” and is generally caused by the occult intrahepatic spread of the primary neoplasm and relate...     

Hepatitis B viral load affects prognosis of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a complex disease that is dually challenging to treat due to underlying chronic liver disease in addition to the cancer itself.The prognosis of patients with HCC is determined by intrahepatic tumor status and reserved hepatic function.Hepatitis B virus(HBV)is an established major risk factor of HCC development,and HBV viral load is being increasingly recognized as a prognostic factor in the presence of established HCC.High HBV viral load may affect the prognosis of HBV-related HCC patients in several ways.First,it is associated with more frequent recurrence of HBV-related HCC after treatment.Second,it is associated with more occurrence and severity of potentially life-threatening HBV reactivation.Last,it is associated with more worsened liver function,which limits the therapeutic options for HBV-related HCC.HBV,directly or indirectly,can induce hepatocarcinogenesis.In patients with a high HBV DNA level and subsequent active hepatitis,adhesion molecules expressed on the sinusoidal cells are up-regulated and may increase intrahepatic metastasis.HCC progression after treatment can lead to a poor prognosis by reducing number of normal functioning hepatocytes.Thus,high HBV viral load can affect the prognosis of patientswith HCC by frequent recurrence after treatment for HCC and deterioration of hepatic function associated with HCC progression.Recent meta-analysis showed that antiviral treatment reduces HCC recurrence and liver-related mortality after curative therapy of HCC.Given the strong relationship between high HBV DNA load and poor survival outcome of HCC patients due to cancer progression,it is expected that long-term antiviral therapy results in the sustained HBV suppression,control of inflammation,reduction in HCC progression,and eventually in improved overall survival.     

肝细胞癌患者肝移植术后肿瘤复发转移的防治

肝细胞癌(HCC)仍是目前发病率较高的消化道肿瘤,肝移植能从根本上切除肿瘤病灶,是HCC综合治疗方案中的主要手段之一。移植后肿瘤的复发和转移问题,是影响受体长期生存的主要因素。近年来,得益于全球范围的技术改进和经验积累,在HCC的诊疗方面取得了的长足的发展和进步。针对HCC肝移植适应证、复发转移预测、肝移植围手术期干预和术后HCC复发的综合治疗等方面进行探讨。     

Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer

Colorectal cancer(CRC) is the most common digestive malignancy across the world. Its first-line treatments applied in the routine clinical setting include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, resistance to therapy has been identified as the major clinical challenge that fails the treatment method, leading to recurrence and distant metastasis. An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance o...     

Epigenetic regulation of insulin-like growth factor axis in hepatocellular carcinoma

The insulin-like growth factor (IGF) signaling pathway is an important pathway in the process of hepatocarcinogenesis, and the IGF network is clearly dysregulated in many cancers and developmental abnormalities. In hepatocellular carcinoma (HCC), only a minority of patients are eligible for curative treatments, such as tumor resection or liver transplant. Unfortunately, there is a high recurrence of HCC after surgical tumor removal. Recent research efforts have focused on targeting IGF axis members in an attempt to find therapeutic options for many health problems. In this review, we shed lights on the regulation of members of the IGF axis, mainly by microRNAs in HCC. MicroRNAs in HCC attempt to halt the aberrant expression of the IGF network, and a single microRNA can have multiple downstream targets in one or more signaling pathways. Targeting microRNAs is a relatively new approach for identifying an efficient radical cure for HCC.     

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.