Curative Treatment For Hepatocellular Carcinoma Research Articles

Beyond Milan criteria – chances and risks of expanding transplantation criteria for HCC patients with liver cirrhosis

Orthotopic liver transplantation (OLT) is, apart from resection, one important curative treatment for hepatocellular carcinoma (HCC) in liver cirrhosis, and especially attractive because it eliminates both the tumor and the underlying liver disease. The application of restrictive inclusion criteria for OLT in HCC patients resulted in favorable long-term recurrence-free survival. These criteria, however, exclude a subgroup of patients which, despite advanced tumor size, demonstrate an acceptable outcome. As a consequence, expansion of the strict Milan criteria has been discussed. However, this will also deteriorate the average outcome of OLT in HCC patients. Considering that we run short of donor organs, more sophisticated prediction models for survival after OLT for HCC patients are needed to identify patients who benefit best from OLT. Neoadjuvant treatment that is frequently applied as a bridging technique for patients on the waiting list for OLT could provide useful information on tumor behavior to better predict the risk of post-OLT tumor recurrence. This might also allow expansion of the Milan criteria to patients with good response to downstaging methods without negatively affecting post-OLT survival. Furthermore, alternative scoring systems have been suggested to identify HCC patients that might still benefit from resection instead of OLT, and molecular tools are being explored to provide predictive information on HCC biology. This review discusses the advantages and risks of extended inclusion criteria for OLT and the currently available data on alternative prediction models and bridging methods in HCC patients.

Predicting prognosis in hepatocellular carcinoma after curative surgery with common clinicopathologic parameters

BackgroundSurgical resection is one important curative treatment for hepatocellular carcinoma (HCC), but the prognosis following surgery differs substantially and such large variation is mainly unexplained. A review of the literature yields a number of clinicopathologic parameters associated with HCC prognosis. However, the results are not consistent due to lack of systemic approach to establish a prediction model incorporating all these parameters.MethodsWe conducted a retrospective analysis on the common clinicopathologic parameters from a cohort of 572 ethnic Chinese HCC patients who received curative surgery. The cases were randomly divided into training (n = 272) and validation (n = 300) sets. Each parameter was individually tested and the significant parameters were entered into a linear classifier for model building, and the prediction accuracy was assessed in the validation setResultsOur findings based on the training set data reveal 6 common clinicopathologic parameters (tumor size, number of tumor nodules, tumor stage, venous infiltration status, and serum α-fetoprotein and total albumin levels) that were significantly associated with the overall HCC survival and disease-free survival (time to recurrence). We next built a linear classifier model by multivariate Cox regression to predict prognostic outcomes of HCC patients after curative surgery This analysis detected a considerable fraction of variance in HCC prognosis and the area under the ROC curve was about 70%. We further evaluated the model using two other protocols; leave-one-out procedure (n = 264) and independent validation (n = 300). Both were found to have excellent prediction power. The predicted score could separate patients into distinct groups with respect to survival (p-value = 1.8e-12) and disease free survival (p-value = 3.2e-7).ConclusionThis described model will provide valuable guidance on prognosis after curative surgery for HCC in clinical practice. The adaptive nature allows easy accommodation for future new biomarker inputs, and it may serve as the foundation for future modeling and prediction for HCC prognosis after surgical treatment.

Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis

A combined antiviral and tumoricidal effect of interferon (IFN) is assumed to occur after resection or ablation of hepatocellular carcinoma (HCC). An electronic search of the Medline, Embase and Central databases from January 1998 to October 2007 was conducted to identify randomized controlled trials evaluating adjuvant effects of IFN after curative treatment of HCC. A meta-analysis was performed to estimate the effects of IFN on 2-year outcome. Seven trials enrolling a total of 620 patients were included in the meta-analysis. Adjuvant treatment with IFN significantly reduced the 2-year mortality rate after curative treatment of HCC, with a pooled risk ratio of 0.65 (95 per cent confidence interval 0.52 to 0.80); P < 0.001) in absence of any significant heterogeneity (I(2) = 0 per cent, P = 0.823 for chi(2)). The effect on reduction of tumour recurrence was less pronounced but still significant (pooled risk ratio 0.86 (95 per cent c.i. 0.76 to 0.97); P = 0.013). IFN had to be discontinued in 8-20 per cent of patients. IFN has a significant beneficial effect after curative treatment of HCC in terms of both survival and tumour recurrence.

Second and third hepatectomies for recurrent hepatocellular carcinoma are justified

Liver resection is the main curative treatment for hepatocellular carcinoma (HCC), but recurrence rates are high. The remnant liver is the most common site of recurrence, but the role of repeat hepatectomy in the treatment of recurrent HCC is controversial. Patients who underwent curative hepatectomy for HCC and subsequent repeat hepatectomy for recurrent HCC between 1990 and 2007 were reviewed retrospectively. Clinicopathological characteristics, and early- and long-term outcomes of patients who had a first, second, third and fourth hepatectomy were compared. Some 1177 patients underwent a first hepatectomy for HCC, and 149, 35 and eight patients respectively had a second, third and fourth hepatectomies for recurrence. There were no significant differences in early postoperative outcomes after first and repeat hepatectomies. Five-year disease-free and overall survival rates after first, second and third hepatectomies were 43.6, 31.8 and 33.8 per cent (P = 0.772), and 52.4, 56.4 and 59.4 per cent (P = 0.879), respectively. Patients undergoing second and third hepatectomies for recurrence had better survival rates than those who did not have a repeat hepatectomy, but not those after fourth hepatectomy. Second and third hepatectomies seem justified for hepatic recurrence of HCC. The role of fourth hepatectomy needs further investigation.

A randomized controlled trial of hepatectomy with adjuvant transcatheter arterial chemoembolization versus hepatectomy alone for Stage III A hepatocellular carcinoma

Hepatectomy is considered as the potentially curative treatment for hepatocellular carcinoma (HCC) and used in some selected Stage IIIA HCC, which include multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s) (UICC TNM staging system, sixth edition). Transcatheter arterial chemoembolization (TACE) was used in retrospective studies to improve the survival outcome of resected HCC. However, its beneficial effect on the survival outcomes of the Stage IIIA patients has not been evaluated. The present study is to evaluate if hepatectomy combining with adjuvant TACE for Stage IIIA HCC result in better long-term survival outcome when compared with hepatectomy alone. From January 2001 to March 2004, we conducted a prospective randomized trial in patients with Stage IIIA HCC (NCT00652587), recruiting 115 Stage IIIA HCC patients to undergo hepatectomy with adjuvant TACE (HT arm) or to undergo hepatectomy alone (HA arm) in our cancer center. Survival outcomes of the two arms were analyzed. The demographic data were well matched between the two arms. There were no significant differences in the morbidity and in-hospital mortality between the two arms of patients. The most significant toxicities associated with adjuvant TACE were nausea/vomiting (54.4%) and transient hepatic toxicity (elevation of aminotransferase, 52.6%). Although there was no significant difference in the rate of recurrence between the two arms (50/57 vs. 56/58, P = 0.094), HT arm seemed to have more proportion of single lesion of recurrent HCC (chi (2) = 3.719, P = 0.054) and more proportion of potential curative therapy for recurrence (chi (2) = 4.456, P = 0.035). Until the time of censor, 92 patients had died. The 1-, 3-, and 5-year overall survival rates and median overall survival for HT arm were 80.7, 33.3, 22.8% and 23.0 months, respectively. The corresponding overall survival rates and median overall survival for HA arm were 56.5, 19.4, 17.5% and 14.0 months, respectively. The difference was significant (stratified log-rank test, P = 0.048). The 1-, 3-, and 5-year disease-free survival rates and median disease-free survival for HT arm were 29.7, 9.3, 9.3% and 6.0 months, respectively; correspondingly, for HA arm were 14.0, 3.5, 1.7% and 4.0 months, respectively (stratified log-rank test, P = 0.004). For Stage IIIA HCC, hepatectomy with adjuvant TACE efficaciously and safely improved survival outcomes when compared with hepatectomy alone.

LAPAROSCOPIC RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA

Radiofrequency ablation (RFA) is one of the best curative treatments for hepatocellular carcinoma in selected patients, and this procedure can be applied either percutaneously or laparoscopically. Although the percutaneous approach is less invasive and is considered the first choice, RFA with laparoscopic guidance is highly recommended for patients with a relative contraindication for percutaneous RFA, such as lesions adjacent to the gastrointestinal tract, gallbladder, bile duct and heart. Recent advances in laparoscopic ultrasound have widened the indication for laparoscopic ablation. In the present paper, we review the indications, advantages, prognosis and safety of laparoscopic RFA for hepatocellular carcinoma.

Transcriptome analysis of liver cancer: Ready for the clinic?

Gene expression in fixed tissues and outcome in hepatocellular carcinoma. Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, Gupta S, Moore J, Wrobel MJ, Lerner J, Reich M, Chan JA, Glickman JN, Ikeda K, Hashimoto M, Watanabe G, Daidone MG, Roayaie S, Schwartz M, Thung S, Salvesen HB, Gabriel S, Mazzaferro V, Bruix J, Friedman SL, Kumada H, Llovet JM, Golub TR.BackgroundIt is a challenge to identify patients who, after undergoing potentially curative treatment for hepatocellular carcinoma, are at greatest risk for recurrence. Such high-risk patients could receive novel interventional measures. An obstacle to the development of genome-based predictors of outcome in patients with hepatocellular carcinoma has been the lack of a means to carry out genomewide expression profiling of fixed, as opposed to frozen, tissue.MethodsWe aimed to demonstrate the feasibility of gene-expression profiling of more than 6000 human genes in formalin-fixed, paraffin-embedded tissues. We applied the method to tissues from 307 patients with hepatocellular carcinoma, from four series of patients, to discover and validate a gene-expression signature associated with survival.ResultsThe expression-profiling method for formalin-fixed, paraffin-embedded tissue was highly effective: samples from 90% of the patients yielded data of high quality, including samples that had been archived for more than 24 years. Gene-expression profiles of tumor tissue failed to yield a significant association with survival. In contrast, profiles of the surrounding nontumoral liver tissue were highly correlated with survival in a training set of tissue samples from 82 Japanese patients, and the signature was validated in tissues from an independent group of 225 patients from the United States and Europe (P = 0.04).ConclusionsWe have demonstrated the feasibility of genomewide expression profiling of formalin-fixed, paraffin-embedded tissues and have shown that a reproducible gene-expression signature correlated with survival is present in liver tissue adjacent to the tumor in patients with hepatocellular carcinoma.[Abstract reproduced by permission of N Engl J Med 2008;359:1995–2004] Gene expression in fixed tissues and outcome in hepatocellular carcinoma. Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, Gupta S, Moore J, Wrobel MJ, Lerner J, Reich M, Chan JA, Glickman JN, Ikeda K, Hashimoto M, Watanabe G, Daidone MG, Roayaie S, Schwartz M, Thung S, Salvesen HB, Gabriel S, Mazzaferro V, Bruix J, Friedman SL, Kumada H, Llovet JM, Golub TR. It is a challenge to identify patients who, after undergoing potentially curative treatment for hepatocellular carcinoma, are at greatest risk for recurrence. Such high-risk patients could receive novel interventional measures. An obstacle to the development of genome-based predictors of outcome in patients with hepatocellular carcinoma has been the lack of a means to carry out genomewide expression profiling of fixed, as opposed to frozen, tissue. We aimed to demonstrate the feasibility of gene-expression profiling of more than 6000 human genes in formalin-fixed, paraffin-embedded tissues. We applied the method to tissues from 307 patients with hepatocellular carcinoma, from four series of patients, to discover and validate a gene-expression signature associated with survival. The expression-profiling method for formalin-fixed, paraffin-embedded tissue was highly effective: samples from 90% of the patients yielded data of high quality, including samples that had been archived for more than 24 years. Gene-expression profiles of tumor tissue failed to yield a significant association with survival. In contrast, profiles of the surrounding nontumoral liver tissue were highly correlated with survival in a training set of tissue samples from 82 Japanese patients, and the signature was validated in tissues from an independent group of 225 patients from the United States and Europe (P = 0.04). We have demonstrated the feasibility of genomewide expression profiling of formalin-fixed, paraffin-embedded tissues and have shown that a reproducible gene-expression signature correlated with survival is present in liver tissue adjacent to the tumor in patients with hepatocellular carcinoma.

Differentiating Early and Late Recurrences After Resection of HCC in Cirrhotic Patients: Implications on Surveillance, Prevention, and Treatment Strategies

Hepatocellular carcinoma (HCC) is one of the most common human malignancies. The majority of HCCs occur in a background of cirrhosis related to hepatitis B virus, hepatitis C virus, or alcoholism. The presence of cirrhosis has significant impact on the management of the cancer. The impairment of liver function as a result of cirrhosis restricts the treatment options, and cirrhosis is also known to predispose to multicentric hepatocarcinogenesis and increase the risk of recurrence after resection of HCC. The advent of liver transplantation and radiofrequency ablation have provided better chances of curative treatment for patients with small HCC detected by screening in recent years; however, hepatic resection remains the mainstay of curative treatment for HCC associated with Child-Pugh class A cirrhosis. While the perioperative safety and long-term survival of liver resection in cirrhotic liver have improved in recent years, the rate of postoperative recurrence of HCC remains high. In more than 80% of the cases of postoperative recurrence after resection of HCC, the recurrent tumors occur in the liver remnant. The mechanisms of intrahepatic recurrence can be either intrahepatic metastasis from the initial tumor or a de novo multicentric tumor. Differentiation of the two has potential implications on surveillance, prevention, and management strategies for recurrence. Clinically, it is impossible to distinguish the two based on imaging appearances. The only definitive way of differentiation is by genetic or molecular studies of the clonal origin of the tumors, which are technically complicated and cannot be used in clinical practice. Hence, several groups of authors have attempted to differentiate intrahepatic metastasis and multicentric recurrence based on the interval of development of recurrence from the time of resection and risk factors associated with the recurrence. These studies have consistently demonstrated that early recurrence within the first 2 years after resection of HCC is likely to be associated with aggressive tumor pathological factors such as high tumor grade, microvascular invasion, and microsatellite lesions, whereas late recurrence is more likely related to underlying liver conditions such as the presence of cirrhosis and hepatitis activity. Such results suggested that early recurrence is most likely the consequence of occult metastasis from the initial tumor, whereas late recurrence more likely represents multicentric tumors. Cucchetti et al. conducted a study on the risk factors associated with early and late recurrence in 204 patients with cirrhosis who had undergone resection of HCC. The authors identified high alpha-fetoprotein level, poorly differentiated tumor, and microvascular invasion as the risk factors for early recurrence within 2 years after resection, and male gender, older age, high transaminase levels, multiple primary tumors, and high alpha-fetoprotein level as risk factors for late recurrence beyond 2 years. These findings are generally in line with those of previous studies. To demonstrate that late recurrence is most likely related to new multicentric tumor development in the cirrhotic liver, the authors further compared the incidence and risk factors of late recurrence in resected patients with the those of development of HCC in a cohort of 150 cirrhotic patients undergoing regular surveillance of HCC. Such data are not available in previous studies and provide a better insight into the risk of late recurrence after resection of HCC in cirrhotic patients. The authors showed that the risk factors for development of HCC in a group of cirrhotic patients undergoing surveillance were similar to the risk Society of Surgical Oncology 2009

Gene Expression in Fixed Tissues and Outcome in Hepatocellular Carcinoma

It is a challenge to identify patients who, after undergoing potentially curative treatment for hepatocellular carcinoma, are at greatest risk for recurrence. Such high-risk patients could receive novel interventional measures. An obstacle to the development of genome-based predictors of outcome in patients with hepatocellular carcinoma has been the lack of a means to carry out genomewide expression profiling of fixed, as opposed to frozen, tissue. We aimed to demonstrate the feasibility of gene-expression profiling of more than 6000 human genes in formalin-fixed, paraffin-embedded tissues. We applied the method to tissues from 307 patients with hepatocellular carcinoma, from four series of patients, to discover and validate a gene-expression signature associated with survival. The expression-profiling method for formalin-fixed, paraffin-embedded tissue was highly effective: samples from 90% of the patients yielded data of high quality, including samples that had been archived for more than 24 years. Gene-expression profiles of tumor tissue failed to yield a significant association with survival. In contrast, profiles of the surrounding nontumoral liver tissue were highly correlated with survival in a training set of tissue samples from 82 Japanese patients, and the signature was validated in tissues from an independent group of 225 patients from the United States and Europe (P=0.04). We have demonstrated the feasibility of genomewide expression profiling of formalin-fixed, paraffin-embedded tissues and have shown that a reproducible gene-expression signature correlated with survival is present in liver tissue adjacent to the tumor in patients with hepatocellular carcinoma.

Bridge Treatments of Hepatocellular Carcinoma in Cirrhotic Patients Submitted to Liver Transplantation

To the Editor We read with great interest the paper ‘‘Efficacy of locoregional ablation therapy of HCC in a population of liver transplanted patients’’ recently published in Digestive Diseases and Sciences [1]. We agree with the authors that there is not clear evidence that the loco-regional ablation therapies (LAT) performed during the waiting time for liver transplantation contain intrahepatic progression of hepatocellular carcinoma (HCC); in fact, controlled randomized trials on this topic are lacking. However, regardless of the size of the treated tumor, radiofrequency ablation (RFA) has been shown to provide complete necrosis in 47–66% of the cases at explant analysis, and these rates increase to 62–78% when considering only HCCs smaller than 3 cm [2–4]. On the other hand, in patients treated by transarterial chemoembolization (TACE), the rate of hepatocellular carcinoma (HCC) complete necrosis has been reported to range between 16% and 27% [5, 6]. Although there is not certain evidence that complete tumor necrosis induced by bridge treatments impacts on survival of HCC patients after LT, it is reasonable to argue that patients without evidence of viable tumor in the explanted liver could have a better prognosis. We think that the rate of tumor complete necrosis reported by Morisco et al. in their series (7%) is surprisingly low, and that this feature is probably related to the treatments performed. In fact, although TACE, RFA, and percutaneous ethanol injection (PEI) are the most widely used bridge therapies for HCC in patients listed for LT and are considered curative treatments for HCC [7], in Morisco et al.’s series only 9 out of 26 patients were treated by TACE or TAE, only 1 with PEI, and none with RFA. On the other hand, the authors included patients treated by therapies either without proven curative efficacy such as epirubicin infusion, or not well specified such as ‘‘lipiodol combined technique’’ or ‘‘131-I labelled’’ that are nor fully explained in the ‘‘Patients and methods’’ section. Based upon these considerations, it is not surprising that in Morisco et al.’s series the recurrence rate of HCC was not significantly different between patients with and without previous LAT (11.5% versus 8.5%). There are no controlled randomized studies comparing the impact of bridge therapies on disease-free survival after LT performed in cirrhotic patients with HCC. However, in the three large previously cited series in which RFA was used as bridge treatment to LT, the rate of tumor recurrence was low, ranging between 0% and 4% [2–4]. Furthermore, in the largest available case-control study comparing HCC patients submitted or not submitted to TACE before LT, a trend for a lower rate of recurrence was found in the treated patients (13% versus 23%) even if this difference did not reach statistical significance [5].

Current approach to down-staging of hepatocellular carcinoma prior to liver transplantation

Orthotopic liver transplantation is currently the best curative treatment for hepatocellular carcinoma within conventional Milan criteria. Recent data have suggested that modest expansion of tumor size limits could still preserve acceptable long-term recurrence-free survival. Down-staging of hepatocellular carcinoma initially exceeding conventional criteria for transplantation provides a unique perspective on tumor biology in that those with more favorable tumor biology are more likely to be successfully down-staged and do well after transplantation. This article reviews the principles and published data on down-staging of hepatocellular carcinoma prior to orthotopic liver transplantation. Several groups have examined the use of loco-regional therapy such as chemoembolization and radiofrequency ablation for tumor down-staging before Orthotopic liver transplantation. According to the latest results from the University of California, San Francisco involving 61 patients with hepatocellular carcinoma exceeding Milan criteria but meeting specific criteria for tumor size and number, 70% were successfully down-staged to within Milan criteria by an intention-to-treat analysis, with no posttransplant recurrence and a 4-year posttransplant survival of 92%. Strictly defined upper limits of tumor size and number for patient inclusion, as well as criteria for response to loco-regional therapy, are essential in achieving excellent posttransplant outcome following tumor down-staging.

Renal Invasion Of Hepatocellular Carcinoma: Report Of A Case

Hepatosellüler karsinomada küratif tedavilerden sonra lokal nüks ya da uzak metastazlar ortaya çıkabilmektedir. Bu yazıda cerrahi tedaviden sonra intrahepatik rekürrensin yanı sıra inferior vena kava, sağ adrenal bez ve sağ böbreğe invazyona neden olan ekstrahepatik tümör gelişiminin saptandığı 47 yaşında bir hasta sunulmakta ve özellikle direk invazyona ikinci olarak değerlendirilen renal tutulumun MR görüntüleme bulguları vurgulanmaktadır.

Racial and Geographic Disparities in the Utilization of Surgical Therapy for Hepatocellular Carcinoma

The incidence of hepatocellular carcinoma (HCC) continues to increase, a trend that will likely continue because of the rising prevalence of chronic hepatitis C infection. This study sought to determine the recent patterns of utilization of surgical therapy (hepatectomy, ablation, or liver transplantation) for HCC from the Surveillance, Epidemiology, and End Results national cancer registry. Data were extracted for 16,121 patients with HCC diagnosed between 1998 and 2004. Twenty-three percent of patients underwent surgical therapy (9.5% resection, 7.8% ablation, 6% transplant); the proportion of patients treated with surgical therapy increased ∼9% over the study period. On multivariate analysis, female sex, younger age, and smaller solitary tumors were associated with increased utilization of surgical therapy. Blacks and Hispanics were 24–27% less likely to receive surgical therapy than white individuals (P < 0.001). Racial and geographic disparities persisted despite the adjustment for Health Service Area and limitation of the cohort to small localized HCC. Blacks were especially disadvantaged in the utilization of liver transplant for small HCC (OR = 0.42, P < 0.001). Further investigation to understand the etiology of these profound racial and geographic disparities is essential to ensure equitable provision of surgical therapies, which provide the only potentially curative treatments for HCC.

Radiofrequency Ablation Combined with Resection Enhances Chance for Curative Treatment of Hepatocellular Carcinoma

Radiofrequency Ablation Combined with Resection Enhances Chance for Curative Treatment of Hepatocellular Carcinoma

Hepatocellular Carcinoma with Indeterminate or False-Negative Findings at Initial MR Imaging: Effect on Eligibility for Curative Treatment—Initial Observations

To retrospectively evaluate the effect of indeterminate or false-negative findings at magnetic resonance (MR) imaging on eligibility for curative treatment of hepatocellular carcinoma (HCC). This HIPAA-compliant retrospective study was approved by the institutional review board; the need for informed consent was waived. Of 166 patients with cirrhosis in whom HCC was detected with MR imaging, 21 (13 men, eight women; mean age, 60 years) had 33 proved HCCs that were not detected on previous MR images obtained 6-24 months earlier. MR imaging included T1-weighted, T2-weighted, and dynamic contrast material-enhanced T1-weighted imaging. Serial MR images and treatment records were reviewed to evaluate nodule growth and the effect of delayed diagnosis on treatment eligibility. Of 33 HCCs in 21 patients, 24 corresponding nodules (73%) were described on previous MR images as benign or indeterminate. Five additional nodules were visible at retrospective evaluation, but only on arterial phase images. The diameters of these 29 visible but indeterminate nodules were initially 0.6-1.9 cm (mean, 1.1 cm) and increased to 0.9-4.5 cm (mean, 1.9 cm) at HCC diagnosis (mean follow-up, 378 days). The mean doubling time was 856 days for diameter and 285 days for volume. All nine HCCs with a delayed diagnosis of less than 1 year were smaller than 3 cm at diagnosis, and the patients had undergone liver transplantation (n=3) or technically successful ablation or embolization (n=6). All 10 subcentimeter indeterminate nodules were smaller than 2 cm at HCC diagnosis, and none progressed to untreatable HCC. Indeterminate nodules smaller than 2 cm did not become untreatable HCC with delayed HCC diagnosis of 6-12 months.

Changes in hepatic functional reserve after percutaneous tumor ablation for hepatocellular carcinoma: long-term follow up for 227 consecutive patients with a single lesion

Percutaneous tumor ablation (PTA), such as ethanol injection, is currently accepted as a potentially curative treatment for hepatocellular carcinoma (HCC). Percutaneous tumor ablation is presumed to be relatively non-invasive, but there are few studies on long-term follow-up of liver function after tumor ablation. Changes in liver functions were monitored in 227 consecutive patients treated for a solitary HCC nodule by PTA between 1993 and 1997. The liver function evaluated based on Child-Turcotte classification prior to the initial treatment was Child A in 119 (52.4%) patients, B in 81(35.7%), and C in 27 (11.9%). The follow-up period was 46 +/- 21 months. The five-year survival rates of patients in Child A, B, and C group after treatment were respectively 76%, 45%, and 43%. Annual shift rate of Child A to Child B was 7%, and that of Child B to Child C was 14%. Tumor recurrence significantly affected aggravation of liver function in Child A (P = 0.002) but not in Child B patients (P = 0.55). Tumor size at initial treatment influenced changes of liver function in Child B group patients (P = 0.009). Preservation of liver function may be essential when treating HCC patients with impaired liver function.

Combined therapy of transcatheter hepatic arterial embolization with intratumoral dendritic cell infusion for hepatocellular carcinoma: clinical safety

The curative treatments for hepatocellular carcinoma (HCC), including surgical resection and radiofrequency ablation (RFA), do not prevent tumour recurrence effectively. Dendritic cell (DC)-based immunotherapies are believed to contribute to the eradication of the residual and recurrent tumour cells. The current study was designed to assess the safety and bioactivity of DC infusion into tumour tissues following transcatheter hepatic arterial embolization (TAE) for patients with cirrhosis and HCC. Peripheral blood mononuclear cells (PBMCs) were differentiated into phenotypically confirmed DCs. Ten patients were administered autologous DCs through an arterial catheter during TAE treatment. Shortly thereafter, some HCC nodules were treated additionally to achieve the curative local therapeutic effects. There was no clinical or serological evidence of adverse events, including hepatic failure or autoimmune responses in any patients, in addition to those due to TAE. Following the infusion of (111)Indium-labelled DCs, DCs were detectable inside and around the HCC nodules for up to 17 days, and were associated with lymphocyte and monocyte infiltration. Interestingly, T lymphocyte responses were induced against peptides derived from the tumour antigens, Her-2/neu, MRP3, hTERT and AFP, 4 weeks after the infusion in some patients. The cumulative survival rates were not significantly changed by this strategy. These results demonstrate that transcatheter arterial DC infusion into tumour tissues following TAE treatment is feasible and safe for patients with cirrhosis and HCC. Furthermore, the antigen-non-specific, immature DC infusion may induce immune responses to unprimed tumour antigens, providing a plausible strategy to enhance tumour immunity.

Low-dose intermittent interferon-alpha therapy for HCV-related liver cirrhosis after curative treatment of hepatocellular carcinoma

To assess the efficacy of low-dose intermittent interferon (IFN) therapy in patients with hepatitis C virus (HCV)-related compensated cirrhosis who had received curative treatment for primary hepatocellular carcinoma (HCC). We performed a prospective case controlled study. Sixteen patients received 3 MIU of natural IFN-alpha intramuscularly 3 times weekly for at least 48 wk (IFN group). They were compared with 16 matched historical controls (non-IFN group). The cumulative rate of first recurrence of HCC was not significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 68.6% vs 80% at 1- and 3-year, P = 0.157, respectively). The cumulative rate of second recurrence was not also significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 35.9% vs 67% at 1- and 3-year, P = 0.056, respectively). Although the difference in the Child-Pugh classification score between the groups at initial treatment of HCC was not significant, the score was significantly worse at the time of data analysis in the non-IFN group than IFN group (7.19 +/- 1.42 vs 5.81 +/- 0.75, P = 0.0008). The cumulative rate of deviation from objects of any treatment for recurrent HCC was also higher in the non-IFN group than IFN group (6.7% and 27% vs 0 and 0% at 1- and 3-year, P = 0.048, respectively). Low-dose intermittent IFN-alpha therapy for patients with HCV-related compensated cirrhosis after curative HCC treatment was effective by making patients tolerant to medical or surgical treatment for recurrent HCC in the later period of observation.

Prolonged, NK Cell-Mediated Antitumor Effects of Suicide Gene Therapy Combined with Monocyte Chemoattractant Protein-1 against Hepatocellular Carcinoma

Tumor recurrence rates remain high after curative treatments for hepatocellular carcinoma (HCC). Immunomodulatory agents, including chemokines, are believed to enhance the antitumor effects of tumor cell apoptosis induced by suicide gene therapy. We therefore evaluated the immunomodulatory effects of a bicistronic recombinant adenovirus vector (rAd) expressing both HSV thymidine kinase and MCP-1 on HCC cells. Using an athymic nude mouse model (BALB/c-nu/nu), primary s.c. tumors (HuH7; human HCC cells) were completely eradicated by rAd followed by treatment with ganciclovir. The same animals were subsequently rechallenged with HCC cells, tumor development was monitored, and the recruitment or activation of NK cells was analyzed immunohistochemically or by measuring IFN-gamma mRNA expression. Tumor growth was markedly suppressed as compared with that in mice treated with a rAd expressing the HSV thymidine kinase gene alone (p < 0.001). Suppression of tumor growth was associated with the elevation of serum IL-12 and IL-18. During suppression, NK cells were recruited exclusively, and Th1 cytokine gene expression was enhanced in tumor tissues. The antitumor activity, however, was abolished either when the NK cells were inactivated with anti-asialo GM1 Ab or when anti-IL-12 and anti-IL-18 Abs were administered. These results indicate that suicide gene therapy, together with delivery of MCP-1, eradicates HCC cells and exerts prolonged NK cell-mediated antitumor effects in a model of HCC, suggesting a plausible strategy to prevent tumor recurrence.

Optimal Initial Treatment for Early Hepatocellular Carcinoma in Patients with Preserved Liver Function: Transplantation or Resection?

Partial hepatic resection has been the mainstay of curative treatment for hepatocellular carcinoma (HCC) in cirrhotic patients with preserved liver function. Liver transplantation for HCC was initially developed as a treatment option for patients with unresectable tumors associated with Child B or C cirrhosis. However, in recent years, some authors have advocated liver transplantation even for resectable early HCC associated with Child A cirrhosis. Whether transplantation or liver resection is the optimal initial treatment for early HCC in compensated cirrhosis depends on the survival results and also the availability of liver grafts. Recent studies comparing liver resection and transplantation for early HCC in Child A cirrhotic patients demonstrated similar long-term survival. While liver transplantation is associated with a lower tumor recurrence rate, this benefit is counteracted by long-term complications such as immunosuppression related infections and neoplasms. Patients put on transplantation waiting list run a significant risk of tumor progression and dropout, while liver resection is immediately applicable to all. A premature liver transplantation may expose patients to the side effects of immunosuppression earlier than necessary. With the current shortage of liver grafts, advocating primary liver transplantation for patients with early HCC associated with compensated cirrhosis will increase waiting time of transplantation and further increases the chance of dropout. Resection first and salvage transplantation for recurrent tumors or liver failure has been shown to be a feasible strategy in the majority of patients, and this appears to be the optimal strategy with the best use of organs.