Conversion to sirolimus immunosuppression in liver transplantation recipients with hepatocellular carcinoma： Report of an initial experience

AIM: To report a retrospective analysis of preliminary results of 36 patients who received sirolimus (SRL, Rapa-mune, rapamycin) in a consecutive cohort of 248 liver allograft recipients. METHODS: Thirty-six liver transplant patients with he-patocellular carcinoma (HCC) who were switched to SRL-based immunosuppression therapy from tacrolimus were enrolled in this study. The patients who were diagnosed as advanced HCC before orthotopic liver transplantation (OLT) were divided into group A (n = 11), those who were found to have HCC recurrence and/or metastasis after OLT were assigned to group B (n=18), and those who developed renal insufficiency caused by calcineurin inhibitor (CNI) were assigned to group C (n = 7) after OLT. RESULTS: The patients were followed up for a median of 10.4 mo (range, 3.8-19.1 mo) after conversion to SRL therapy and 12.3 mo (range, 5.1-34.4 mo) after OLT. Three patients developed mild acute cellular rejection 2 wk after initiating SRL therapy, which was fully reversed after prednisolone pulse therapy. In group A, only 1 patient was found to have HCC recurrence and metastasis 12 mo after OLT. In group B, 66.7% (12/18) patients (2 with progressive tumor, 7 with stable tumor and 3 without tumor) were still alive due to conversing to SRL and/ or resection for HCC recurrence at the end of a median follow-up of 6.8 mo post conversion and 10.7 mo post-transplant. In group C, no HCC recurrence was demonstrated in 7 patients, and renal function became normal after SRL therapy. Thrombocytopenia (n = 2), anemia (n = 8), and oral aphthous ulcers (n = 7) found in our cohort were easily manageable. CONCLUSION: The conversion to SRL-based immuno-suppression may inhibit the recurrence and metastasis of HCC and improve CNI-induced renal insufficiency in OLT patients with HCC.     

Hepatic intra-arterial infusion of yttrium-90 microspheres in the treatment of recurrent hepatocellular carcinoma after liver transplantation： A case report

INTRODUCTION Strict criteria developed to select patients with hepatocellular carcinoma (HCC) for liver transplantation have increased the survival and decreased the recurrence of tumor after transplantation[1]. However, tumor recurrence and subsequent mo…     

Systemic chemotherapy for hepatocellular carcinoma in non-cirrhotic liver： A retrospective study

AIM： To investigate the efficacy and toxicity of systemic chemotherapy in a retrospective study of patients with hepatocellular carcinoma （HCC） occurring in normal or fibrotic liver without cirrhosis.
METHODS： Twenty-four patients with metastatic or locally advanced HCC in a normal or a fibrotic liver were given systemic chemotherapy （epirubicin, cisplatin and 5-fluorouracil or epirubicin, cisplatin and capecitabine regimens）. Tumor response, time to progression, survival, and toxicity were evaluated.
RESULTS： There were 7 women and 17 men, mean age 54 ± 10 years; 18 patients had a normal liver and 6 had a fibrotic liver （F1/F2 on biopsy）. Mean tumor size was 14 cm, 5 patients had portal vein thrombosis and 7 had metastasis. Patients received a median of 4 chemotherapy sessions. Overall tolerance was good. There were 5 partial responses （objective response rate = 22%）, and tumor control rate was 52%. Second line surgical resection was possible in two patients. Median survival was 11 mo, and 1- and 2-year overall survival rates were 50% ± 10% and 32 ± 11%, respectively.
CONCLUSION： In patients with HCC in a non-cirrhotic liver, chemotherapy was well tolerated and associated with an objective response rate of 22%, including two patients who underwent secondary surgical resection.     

Activation of c-Yes in hepatocellular carcinoma： A preliminary study

TO THE EDITOR Hepatocellular carcinoma (HCC) is thought to develop through a multistep process[1]. A long history of viral hepatitis or prolonged exposure to environmental toxins predisposes liver cells to mutations of the genes critical in the control of hepatocyte growth. In fact, both activation of cellular oncogenes and inactivation of tumorsuppressor genes are involved in the development of HCC. Activation of oncogenes by hepatitis virus integration has been shown in the woodchuck animal model[2],although the significance of this finding in human hepatocarcinogenesis is still under investigation.     

Coexistence of hepatocellular carcinoma and gastrointestinal stromal tumor： A case report

Malignant gastrointestinal stromal tumors(GIST)are raremesenchymal tumors originating from the wall of thegastrointestinal tract.Their coexistence with other tumorsoriginating from other germ layers is unique.We havereported a case of a 63-year-old GIST patient presentingas an epigastric mass associated with hepatic tumor.Histologically,the mesenteric tumor was composed ofspindle cells showing both neural and smooth muscledifferentiation.Immunohistochemical examinationshowed positive staining for CD117,vimentin,S-100,and SMA,while CD34 antigen was negative.The hepatictumor was diagnosed as hepatocellular carcinoma(HCC).To the best of our knowledge,this is the first case ofGIST and HCC coexistence.The rarity of the case,however,should not lead to ignoring such a possibility indifferential diagnosis.     

Role of AFP mRNA expression in peripheral blood as a predictor for postsurgical recurrence of hepatocellular carcinoma： A systematic review and meta-analysis

AIM: To identify the role of alpha-fetoprotein (AFP) mRNA expression in peripheral blood one week after surgery as a predictor for recurrence of hepatocellular carcinoma (HCC). METHODS: Published studies fulfilling the selection criteria were identified by searching several databases online. After a methodology assessment using a quality scale designed by European Lung Cancer Working Party, data in each research were aggregated by means of meta-analysis. RESULTS: Altogether 368 cases were included in the 9 selected studies, which fulfilled the selection criteria. The quality scores ranged from 35% to 84% with a median score of 55%. The 'design' subscore had the lowest median value (38%). By aggregating the data, a high x2 value (77.576) was presented. The fail-safe number was 136 and 64 for P= 0.05 and 0.01, respectively. CONCLUSION: AFP mRNA expression in peripheral blood 1 wk after surgery correlated with the recurrence of HCC and was a good predictor for tumor recurrence.     

Disseminated tumor cells homing into rats′ liver： A new possible mechanism of HCC recurrence

AIM: To detect the origin of hepatocellular carcinoma (HCC) recurring and attempt to propose a new recurrent mechanism. METHODS: Orthotopic liver allotransplantation was performed on male rats with HCC- induced by diethylnitrosamine using female donors. Metastatic tumors in transplanted livers were obtained. A DNA probe that exhibits specificity for the rat Y chromosome was generated by using a set of primers specific to murine sry gene. In situ hybridization (ISH) for Y chromosome was used to detected the origin of HCC recurring. Male HCC tissue was designed to be positive control. ISH on female tissue and using non-labeled with DIG probe was thought to be negative control. RESULTS: Positive marks were seen through ISH for Y chromosome in recurrent tumor tissue and positive control. No signal was detected in both negative controls. CONCLUSION: Recurrent HCC after liver transplantation originated from disseminated tumor cells in recipients. Extrahepatic cells homing into liver may be a new HCC recurrence mechanism. Likewise, it implicates that this mechanism is responsible for HCC recurring after hepatectomy.     

Association between the presence of H pylori in the liver and hepatocellular carcinoma： A meta-analysis

AIM： To evaluate the arguments for and against the possible roles of H pylori in hepatocellular carcinoma （HCC）.
METHODS： We performed a systematic review of all relevant studies published in the literature. A total of 103 clinical trials and reports were identified, but only 10 trials qualified under our selection criteria. A metaanalysis was carried out by a biostatistician according to the Cochrane Reviewers＇ Handbook recommended by The Cochrane Collaboration.
RESULTS： Nine case-control studies and one retrospective cross sectional study were included in the final analysis. Overall the prevalence of H pylori infection was 53.3% （129 of 242） in cases and 10.4% （29 of 280） in controls, and the summary odds ratio for the association of H pylori infection with the risk for HCC （using the fixed-effects model, which accounted for the homogeneity across the 10 studies） was determined to be 13.63 （95% CI, 7.90-23.49）.
CONCLUSION： Our analysis showed a positive association between F1 pylori infection and the risk of HCC, with an indication of possible publication bias and possible confounders due to study designs that showed results of less pronounced associations.     

Superantigen-SEA gene modified tumor vaccine for hepatocellular carcinoma： An in vitro study

AIM: To construct an eukaryotic superantigen gene expression vector containing the recombinant gene of SEA and CD80 molecule transmembrane region (CD80TM), and to express staphylococcus enterotoxin A (SEA) on the membrane of hepatocellular carcinoma (HCC) cell to form a superantigen gene modified tumor vaccine for HCC. METHODS: SEA and linker-CD80TM gene were amplified through PCR from plasmid containing cDNA of SEA and CD80. Gene fragments were then subcloned into the multiple cloning sites of retroviral vector pLXSN. Recombinant plasmid was transferred into HepG2 cells mediated with lipofectamine, positive clones were selected in culture medium containing G418. RT-PCR and indirect immunofluorescence studies confirmed that SEA was expressed specifically on HCC cell membrane. INFgamma-ELISPOT study demonstrated that SEA protein was expressed on the membrane of HCC cells. Cytotoxicity of HepG2-SEA primed CTLs (SEA-T) was analyzed by (51)Cr release assay. T cells cultured with rhIL-2 (IL-2-T) were used as control. RESULTS: Restriction digestion and sequence analyses confirmed the correctness of length, position and orientation of inserted fusion genes. SEA was expressed on the surface of HepG2 cells, HepG2-SEA had strong stimulating effect on production of HepG2 specific CTL (P<0.001). SEA-T had enhanced cytotoxicity to HepG2 cells (P<0.05). CONCLUSION: Tumor cell membrane expressed superantigen can be used to reinforce the immune effect of tumor cell vaccine for HCC, which provides a new method of the enhanced active immunotherapy for HCC.     

Liver transplantation for hepatocellular carcinoma on cirrhosis: strategies to avoid tumor recurrence

Hepatocellular carcinoma(HCC) is one of the most frequent neoplasms worldwide and in most cases it is associated with chronic liver disease.Liver transplantation(LT) is potentially the optimal treatment for those patients with HCC who have a poor functional hepatic reserve due to their underlying chronic liver disease.However,due to the limited availability of donors,only those patients whose oncologic profile is favorable can be considered for LT.Despite the careful selection of candidates based on strict ...     

Liver transplantation for hepatocellular carcinoma:Role of inflammatory and immunological state on recurrence and prognosis

Criteria for liver transplantation(LT)for hepatocellular carcinoma(HCC)and post-LT indicators of prognosis are historically based on the measurement of the tumor mass.Recently,high throughput technologies have increased the prediction of recurrence,but these tools are not yet routinely available.The interaction between HCC and the immune system has revealed an imbalance of lymphocyte phenotypes in the peritumoral tissue,and the increase of regulatory T cells with respect to cytotoxic lymphocytes has been linked to a higher rate of post-LT HCC recurrence.Moreover,some inflammatory markers have shown good reliability in predicting cancer reappearance after surgery,as a result of either a systemic inflammatory response or a decreased capacity of the organism to control the tumor growth.Among these markers,the neutrophil-tolymphocyte ratio appears to be the most promising and easily available serum parameter able to predict HCC recurrence after LT and following other types of treatment,although the exact mechanisms determining its elevation have not been clarified.Post-LT immunosuppression may impact on cancer control,and the exposure to high levels of calcineurin inhibitors or other immunusuppressants has recently emerged as a negative prognostic factor for HCC recurrence and patient survival.Despite the absence of prospective randomized trials,inhibitors of the mammalian target of rapamycin have been shown to be associated with lower rates of tumor recurrence compared to other immunosuppressors,suggesting their use especially in patients with HCC exceeding the conventional indication criteria for LT.     

Review on immunosuppression in liver transplantation

The optimal level of immunosuppression in solid organ transplantation, in particular for the liver, is a delicate balance between the benefit of preventing rejection and the adverse side effects of immunosuppression. There is uncertainty about when this level is achieved in any individual recipient. Immunosuppression regimens vary between individual centers and changes with time as new agents and data are available. Presently concerns about the adverse side effects of calcineurin inhibitor, the main class of immunosuppressive agents used in liver transplantation (LT), has led to consideration of the use of antibody induction therapies for patients at higher risk of developing adverse side effects. The longevity of the transplanted organ is potentially improved by better management of rejection episodes and special consideration for tailoring of immunosuppression to the individual with viral hepatitis C, hepatocellular carcinoma or pregnancy. This review provides an overview of the current strategies for post LT immunosuppression and discusses modifications to consider for special patient populations.     

Impact of non-oncological factors on tumor recurrence after liver transplantation in hepatocellular carcinoma patients

Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver and is one of the leading causes of cancer-related death worldwide. Liver transplantation (LT) has become one of the best curative therapeutic options for patients with HCC, although tumor recurrence after LT is a major and unaddressed cause of mortality. Furthermore, the factors that are associated with recurrence are not fully understood, and most previous studies have focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein, and the tumor stage outside of the Milan criteria. Thus, little attention has been given to factors that are not directly related to HCC (i.e., “non-oncological factors”), which have emerged as predictors of tumor recurrence. This review was performed to assess the effects of non-oncological factors on tumor recurrence after LT. The identification of these factors may provide new research directions and clinical strategies for the prophylaxis and surveillance of tumor recurrence after LT, which can help reduce recurrence and improve patient survival.     

Early steroid withdrawal after liver transplantation for hepatocellular carcinoma

AIM: To evaluate the impact of early steroid withdrawal on the incidence of rejection, tumor recurrence and complications after liver transplantation for advanced- stage hepatocellular carcinoma. METHODS: Fifty-four patients underwent liver transplantation for advanced-stage hepatocellular carcinoma from April 2003 to June 2005. These cases were divided into a steroid-withdrawal group (group A, n = 28) and a steroid-maintenance group (group B, n = 26). In group A, steroid was withdrawn 3 mo after transplantation. In group B, steroid was continuously used postoperatively. The incidence of rejection, 6-mo and 1-year recurrence rate of carcinoma, 1-year survival rate, mean serum tacrolimus trough level, and liver and kidney function were compared between the two groups. RESULTS: In the two groups, no statistical difference was observed in the incidence of rejection (14.3 vs 11.5%, P > 0.05), mean serum tacrolimus trough levels (6.9 ± 1.4 vs 7.1 ± 1.1 μg/L, P > 0.05), liver and kidney function after 6 mo [alanine aminotransferase (ALT): 533 ± 183 vs 617 ± 217 nka/L, P > 0.05; creatinine: 66 ± 18 vs 71 ± 19 μmol/L, P > 0.05], 6-mo recurrence rate of carcinoma (25.0 vs 42.3%, P > 0.05), and 1-year survival rate (64.2 vs 46.1%, P > 0.05). The 1-year tumor recurrence rate (39.2 vs 69.2%, P < 0.05), serum cholesterol level (3.9 ± 1.8 vs 5.9 ± 2.6 mmol/L, P < 0.01) and fasting blood sugar (5.1 ± 2.1 vs 8.9 ± 3.6 mmol/L, P < 0.01) were signifi cantly different. These were lower in the steroid-withdrawal group than in the steroid- maintenance group. CONCLUSION: Early steroid withdrawal was safe after liver transplantation in patients with advanced-stage hepatocellular carcinoma. When steroids were withdrawn 3 mo post-operation, the incidence of rejection didnot increase, and there was no demand to maintain tacrolimus at a high level. In contrast, the tumor recurrence rate and the potential of adverse effects decreased signifi cantly. This may have led to an increase in long-term survival rate.     

Post-transplant infection improves outcome of hepatocellular carcinoma patients after orthotopic liver transplantation

BACKGROUND Tumor recurrence after orthotopic liver transplantation(OLT) remains a serious threat for long-term survival of the recipients with hepatocellular carcinoma(HCC), since very few factors or measures have shown impact on overcoming HCC recurrence after OLT. Postoperative infection suppresses tumor recurrence and improves patient survival in lung cancer and malignant glioma probably via stimulating the immune system. Post-transplant infection(PTI), a common complication, is deemed to be harmful for the liver transplant recipients from a short-term perspective. Nevertheless, whether PTI inhibits HCC recurrence after OLT and prolongs the long-term survival of HCC patients needs to be clarified.AIM To investigate the potential influence of PTI on the survival and tumor recurrence of patients with HCC after OLT.METHODSA total of 238 patients with HCC who underwent OLT between August 2002 and July 2016 at our center were retrospectively included and accordingly subdivided into a PTI group(53 patients) and a non-PTI group(185 patients). Univariate analyses, including the differences of overall survival(OS), recurrence-free survival(RFS), and post-recurrence survival(PRS), between the PTI and non-PTI subgroups as well as survival curve analysis were performed by the KaplanMeier method, and the differences were compared using the log rank test. The variables with a P-value 0.1 in univariate analyses were included in the multivariate survival analysis by using a Cox proportional-hazards model.RESULTS The 1-, 3-, and 5-year OS and RFS rates of the whole cohort were 86.6%, 69.0%,and 63.6%, and 75.7%, 60.0%, and 57.3%, respectively. The 1-, 3-, and 5-year OS rates for the PTI patient group(96.0%, 89.3%, and 74.0%) were significantly higher than those for the non-PTI group(84.0%, 63.4%, and 60.2%)(P = 0.033).The absence of PTI was an independent risk factor for dismal OS(relative risk[RR] = 2.584, 95%CI: 1.226-5.449) and unfavorable RFS(RR = 2.683, 95%CI: 1.335-5.390). Subgroup analyses revealed that PTI remarkably improved OS(P = 0.003)and RFS(P = 0.003) rates of HCC patients with vascular invasion(IV), but did not impact on OS(P = 0.404) and RFS(P = 0.304) of patients without VI. Among the patients who suffered post-transplant tumor recurrence, patients with PTI showed significantly better OS(P = 0.026) and PRS(P = 0.042) rates than those without PTI.CONCLUSION PTI improves OS and RFS of the transplant HCC patients at a high risk for posttransplant death and tumor recurrence, which is attributed to suppressive effect of PTI on HCC recurrence.     

Efficacy of immunosuppression monotherapy after liver transplantation: A meta-analysis

AIM: To assess the advantages and disadvantages of immunosuppression monotherapy after transplantation and the impact of monotherapy on hepatitis C virus (HCV) recurrence.METHODS: Articles from Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, including non-English literature identified in these databases, were searched up to January 2013. We included randomized clinical trials comparing various immunosuppression monotherapy and prednisone-based immunosuppression combinations for liver transplantation. The modified Jadad scale score or the Oxford quality scoring system was used. Meta-analyses were performed with weighted random-effects models.RESULTS: A total of 14 randomized articles including 1814 patients were identified. Eight trials including 1214 patients compared tacrolimus monotherapy (n = 610) vs tacrolimus plus steroids or triple therapy regarding acute rejection and adverse events (n = 604). Five trials, including 285 patients, compared tacrolimus monotherapy (n = 143) vs tacrolimus plus steroids or triple therapy regarding hepatitis C recurrence (n = 142). Four trials including 273 patients compared cyclosporine monotherapy (n = 148) vs cyclosporine and steroids regarding acute rejection and adverse events (n = 125). Two trials including 170 patients compared mycophenolate mofetil monotherapy (n = 86) vs combinations regarding acute rejection (n = 84). There were no significant differences in the acute rejection rates between tacrolimus monotherapy (RR = 1.04, P = 0.620), and cyclosporine monotherapy (RR = 0.89, P = 0.770). Mycophenolate mofetil monotherapy had a significant increase in the acute rejection rate (RR = 4.50, P = 0.027). Tacrolimus monotherapy had no significant effects on the recurrence of hepatitis C (RR = 1.03, P = 0.752). More cytomegalovirus infection (RR = 0.48, P = 0.000) and drug-related diabetes mellitus (RR = 0.54, P = 0.000) were observed in the immunosuppression combination therapy groups.CONCLUSION: Tacrolimus and cyclosporine monotherapy may be as effective as immunosuppression combination therapy. Mycophenolate mofetil monotherapy was not considerable. Tacrolimus monotherapy does not increase recurrence of HCV.     

Overview of immunosuppression in liver transplantation

Continued advances in surgical techniques and immunosuppressive therapy have allowed liver transplantation to become an extremely successful treatment option for patients with end-stage liver disease. Beginning with the revolutionary discovery of cyclosporine in the 1970s, immunosuppressive regimens have evolved greatly and current statistics confirm one-year graft survival rates in excess of 80%. Immunosuppressive regimens include calcineurin inhibitors, anti-metabolites, mTOR inhibitors, steroids and antibody-based therapies. These agents target different sites in the T cell activation cascade, usually by inhibiting T cell activation or via T cell depletion. They are used as induction therapy in the immediate peri- and post-operative period, as long-term maintenance medications to preserve graft function and as salvage therapy for acute rejection in liver transplant recipients. This review will focus on existing immunosuppressive agents for liver transplantation and consider newer medications on the horizon.     

肝移植术后原发性肝癌复发与乙型肝炎病毒再感染的关系

目的 探讨肝移植术后原发性肝癌复发与HBV再感染的关系.方法 对2004年1月-2008年12月在中山大学附属第三医院因乙型肝炎相关性终末期肝病行肝移植手术并长期随访的340例患者回顾性分析.患者被列入肝移植等待名单后给予核苷(酸)类似物抗病毒治疗,术中和术后均给予核苷(酸)类似物联合低剂量乙型肝炎免疫球蛋白进行预防.术后定期随访并监测患者HBV再感染的发生率及生存率,用多因素COX回归分析筛选出影响术后HBV再感染的危险因素.计量资料用t检验、计数资料用x2检验进行统计学处理.用Kaplan-Meier方法进行生存率分析,对HBV再感染危险因素用COX多因素回归分析,对HBV再感染与原发性肝癌复发的时间进行Spearman线性相关分析.结果 340例患者术后发生HBV再感染33例,术后1、3、5年再感染率分别为7%、10%、13%.HBV再感染的时间为1～21个月,中位数为5个月.原发病为原发性肝癌(风险比为2.98;95%可信区间为1.08～8.25,P＜0.05)、术前HBV DNA载量＞5log10拷贝/ml(风险比为3.99;95%可信区间为1.85～8.62,P＜0.01)是发生HBV再感染的危险因素.原发性肝癌复发者HBV再感染发生率高于未复发者,分别为27.9%和8.7%(风险比为4.58; 95%可信区间为1.88～11.12;P＜0.01).12例患者肝移植术后发生HBV再感染和原发性肝癌复发,两者的复发时间具有相关性(r=0.583,P＜0.05).结论肝移植术后原发性肝癌复发是HBV再感染的危险因素.

Abstract：

Objective To investigate the relationship between hepatocellular carcinoma (HCC)recurrence and hepatitis B virus (HBV) recurrence. Method The clinical data of 340 patients underwent liver transplantation due to HBV related end-stage liver disease and received long-term follow up in our hospital from Jan 2004 to Dec 2008 were retrospectively analyzed. All patients received nucleoside analogues therapy formally before entering into the waiting list and nucleoside analogues combined low-dose HBIG therapy during and after transplantation. Patients were regularly followed up at the outpatient, monitoring the HBV recurrence and survival. Multivariate Cox regression analysis was used to evaluate the risk factors for hepatitis recurrence. Result 33 patients suffered from HBV recurrence post transplantation.The 1-, 3- and 5- year recurrence rates were 7.0%, 10% and 13% respectively. The median HBV recurrence time was 5 months (1-21 months). COX regression analysis revealed that risk factors for HBV recurrence were HCC (HR = 2.98; 95% CI 1.08-8.25; P＜0.05) and pre-transplantation HBV-DNA load over 5 log10 copies/ml (HR = 3.99; 95% CI 1.85-8.62; P＜0.01). Further stratified analysis showed that patients who suffered from carcinoma recurrence had a higher incidence of HBV recurrence than those who did not, which were 27.9% and 8.7% (HR =- 4.58;95% CI 1.88-11.12; P＜0.01) respectively. 12 patients suffered from both HCC and HBV recurrence. Spearman correlation analysis demonstrated a strong correlation between HBV and HCC recurrence times (r= 0.583, P＜0.05). Conclusion Post transplantation HCC recurrence is a risk factor for HBV recurrence.