Helicobacter Species and Hepato-Biliary Tract Malignancies: A Systematic Review and Meta-Analysis.

Helicobacter species may cause chronic inflammation of the biliary tract, but its relationship with cancer is controversial. We performed a systematic review and meta-analysis to evaluate the association between Helicobacter species and hepatobiliary tract malignancies. Twenty-six studies (4083 patients) were included in qualitative synthesis, and 18 studies (n = 1895 qualified for meta-analysis. All studies were at high-intermediate risk of bias. Most studies combined several direct microbiological methods, mostly PCR (23 studies), culture (8 studies), and/or CLOtest (5 studies). Different specimens alone or in combination were investigated, most frequently bile (16 studies), serum (7 studies), liver/biliary tissue (8 studies), and gastric tissue (3 studies). Patients with Helicobacter species infection had an increased risk of hepatobiliary tract malignancies (OR = 3.61 [95% CI 2.18-6.00]; p < 0.0001), with high heterogeneity in the analysis (I2 = 61%; p = 0.0003). This effect was consistent when Helicobacter was assessed in bile (OR = 3.57 [95% CI 1.73-7.39]; p = 0.0006), gastric tissue (OR = 42.63 [95% CI 5.25-346.24]; p = 0.0004), liver/biliary tissue (OR = 4.92 [95% CI 1.90-12.76]; p = 0.001) and serum (OR = 1.38 [95% CI 1.00-1.90]; p = 0.05). Heterogeneity was reduced in these sub-analyses (I2 = 0-27%; p = ns), except for liver/biliary tissue (I2 = 57%; p = 0.02). In conclusion, based on low-certainty data, Helicobacter species chronic infection is associated with a tripled risk of hepatobiliary tract malignancy. Prospective studies are required to delineate public health interventions.

Strategies to reduce hepatitis C virus recurrence after liver transplantation.

Hepatitis C virus (HCV) is a major health problem that leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma, being the most frequent indication for liver transplantation in several countries. Unfortunately, HCV re-infects the liver graft almost invariably following reperfusion, with an accelerated history of recurrence, leading to 10%-30% of patients progressing to cirrhosis within 5 years of transplantation. In this sense, some groups have even advocated for not re-transplanting this patients, as lower patient and graft outcomes have been reported. However, the management of HCV recurrence is being optimized and several strategies to reduce post-transplant recurrence could improve outcomes, decrease the rate of re-transplantation and optimize the use of available grafts. Three moments may be the focus of potential actions in order to decrease the impact of viral recurrence: the pre-transplant moment, the transplant environment and the post-transplant management. In the pre-transplant setting, it is not well established if reducing the pre transplant viral load affects the risk for HCV progression after transplant. Obviously, antiviral treatment can render the patient HCV RNA negative post transplant but the long-term benefit has not yet been fully established to justify the cost and clinical risk. In the transplant moment, factors as donor age, cold ischemia time, graft steatosis and ischemia/reperfusion injury may lead to a higher and more aggressive viral recurrence. After the transplant, discussion about immunosuppression and the moment to start the treatment (prophylactic, pre-emptive or once-confirmed) together with new antiviral drugs are of interest. This review aims to help clinicians have a global overview of post-transplant HCV recurrence and strategies to reduce its impact on our patients.

Diagnosis and management of bacterial infections in decompensated cirrhosis.

Bacterial infections are one of the most frequent complications in cirrhosis and result in high mortality rates. Patients with cirrhosis have altered and impaired immunity, which favours bacterial translocation. Episodes of infections are more frequent in patients with decompensated cirrhosis than those with compensated liver disease. The most common and life-threatening infection in cirrhosis is spontaneous bacterial peritonitis followed by urinary tract infections, pneumonia, endocarditis and skin and soft-tissue infections. Patients with decompensated cirrhosis have increased risk of developing sepsis, multiple organ failure and death. Risk factors associated with the development of infections are severe liver failure, variceal bleeding, low ascitic protein level and prior episodes of spontaneous bacterial peritonitis (SBP). The prognosis of these patients is closely related to a prompt and accurate diagnosis. An appropriate treatment decreases the mortality rates. Preventive strategies are the mainstay of the management of these patients. Empirical antibiotics should be started immediately following the diagnosis of SBP and the first-line antibiotic treatment is third-generation cephalosporins. However, the efficacy of currently recommended empirical antibiotic therapy is very low in nosocomial infections including SBP, compared to community-acquired episodes. This may be associated with the emergence of infections caused by Enterococcus faecium and extended-spectrum ß-lactamase-producing Enterobacteriaceae, which are resistant to the first line antimicrobial agents used for treatment. The emergence of resistant bacteria, underlines the need to restrict the use of prophylactic antibiotics to patients with the greatest risk of infections. Nosocomial infections should be treated with wide spectrum antibiotics. Further studies of early diagnosis, prevention and treatment are needed to improve the outcomes in patients with decompensated cirrhosis.

Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C.

BACKGROUND: The widely-accepted treatment outcome for chronic hepatitis C is the sustained viral response (that is, no measurable viral RNA in blood six months after treatment). However, this surrogate outcome (as well as the previously employed biochemical and histologic ones) has never been validated. This situation exists because there are very few randomized clinical trials that have used clinical events (mortality or manifestations of decompensated cirrhosis) as outcomes, because those clinical events only occur after many years of infection. Patients in whom initial therapy fails to produce sustained viral responses do become potential candidates for retreatment; some of these individuals are not candidates for ribavirin or protease inhibitors and consideration could be given to retreatment with interferon alone. OBJECTIVES: To assess the benefits and harms of interferon monotherapy retreatment in chronic hepatitis C patients and to validate the currently employed surrogate outcomes in this group of patients. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until 16 August 2012. SELECTION CRITERIA: Randomized trials comparing interferon versus placebo or no treatment in chronic hepatitis C nonresponders and relapsers to previous interferon. DATA COLLECTION AND ANALYSIS: The primary outcomes were mortality (all-cause and hepatic), quality of life, and adverse events. Secondary outcomes were liver-related morbidity, sustained viral responses, biochemical responses, histologic improvements, and costs. We used both fixed-effect and random-effects model meta-analyses, reporting only the former if no difference existed. MAIN RESULTS: Seven trials were identified. Two of them were at low risk of bias (the HALT-C and EPIC3 trials) and included 1676 patients. Both of these trials addressed the role of long-term low-dose pegylated interferon therapy in patients with severe fibrosis (demonstrated on liver biopsy) and were designed to assess the clinical outcomes. The remaining five trials included 300 patients and were at high risk of bias. Based on all trials reporting the outcomes, no significant difference was observed in either all-cause mortality (78/843 (9.3%) versus 62/867 (7.2%); risk ratio (RR) 1.30, 95% confidence interval (CI) 0.95 to 1.79; 3 trials) or hepatic mortality (41/532 (7.7%) versus 40/552 (7.2%); RR 1.07, 95% CI 0.70 to 1.63; 2 trials); however, when only the two trials at low risk of bias were combined, all-cause mortality was significantly higher in the recipients of the pegylated interferon (78/828 (9.4%) versus 57/848 (6.7%); RR 1.41, 95% CI 1.02 to 1.96) although trial sequential analysis could not exclude the possibility of random error. There was less variceal bleeding in the recipients of the interferon (4/843 (0.5%) versus 18/867 (2.1%); RR 0.24, 95% CI 0.09 to 0.67; 3 trials), although again trial sequential analysis could not exclude the presence of a type I error and the effect could not be confirmed in a random-effects model meta-analysis. No significant differences were seen with regard to the development of ascites, encephalopathy, hepatocellular carcinoma, or the need for liver transplantation. One trial reported quality of life data; the pain score was significantly worse in the recipients of the pegylated interferon. Adverse effects tended to be more common in the interferon recipients; the ones that were significantly more common included hematologic complications, infections, flu-like symptoms, and rash. The recipients of interferon had significantly more sustained viral responses (20/557 (3.6%) versus 1/579 (0.2%); RR 15.38, 95% CI 2.93 to 80.71; 4 trials) and a type I error was excluded by trial sequential analysis. The METAVIR activity score also improved (36/55 (65%) versus 20/46 (43.5%); RR 1.49, 95% CI 1.02 to 2.18; 2 trials). No significant differences were seen with regard to histologic fibrosis assessments. AUTHORS' CONCLUSIONS: The clinical data were limited to patients with histologic evidence of severe fibrosis who were retreated with pegylated interferon. In this scenario, retreatment with interferon did not appear to provide significant clinical benefit and, when only the trials at low risk of bias were considered, retreatment for several years may even have increased all-cause mortality. Such treatment also produced adverse events. On the other hand, the treatment did result in improvement in some surrogate outcomes, namely sustained viral responses and histologic evidence of inflammation. Interferon monotherapy retreatment cannot be recommended for these patients. No clinical data are available for patients with less severe fibrosis. The sustained viral response cannot be used as a surrogate marker for hepatitis C treatment in this clinical setting with low sustained viral response rates and needs to be validated in others in which higher sustained viral response rates are reported.

Serum ferritin is a discriminant marker for both fibrosis and inflammation in histologically proven non-alcoholic fatty liver disease patients.

INTRODUCTION: Differentiation between steatosis and non-alcoholic steatohepatitis (NASH) in non-alcoholic fatty liver disease (NAFLD) is important as NASH progress to cirrhosis. No specific laboratory/imaging technique exists either to diagnose NASH or to select patients for liver biopsy. PATIENTS AND METHODS: We evaluated serum ferritin and the features of metabolic syndrome with respect to histological inflammation and/or fibrosis in NAFLD patients. The Kleiner scoring system was used to classify NAFLD in consecutive liver biopsies. One hundred and eleven patients: median age 52.6, 64 males, obesity 62, diabetes mellitus (DM) 58, arterial hypertension 26 and hyperlipidaemia 40%. RESULTS: Histologically, 40.7 had fatty liver, 30.6% had borderline NASH, 28.7% had NASH and 11% had cirrhosis. Multivariate regression showed that diabetes, serum ferritin concentrations, body mass index (BMI) and AST were independently associated with NASH: together, the areas under the receiver operating characteristic (AUROC) was 0.91 (95% confidence interval 0.86-0.96); fibrosis was associated with ferritin concentrations and BMI: AUROC 0.87, portal inflammation with ferritin and DM: AUROC 0.82, while lobular inflammation was associated with BMI, DM and ferritin: AUROC 0.85. CONCLUSION: Serum ferritin concentrations and BMI are strongly associated with fibrosis, portal and lobular inflammation in NAFLD patients. Both ferritin and BMI are potential discriminant markers to select patients for liver biopsy and are associated with inflammation and fibrosis.

Comparison of cystatin C and creatinine-based glomerular filtration rate formulas with 51Cr-EDTA clearance in patients with cirrhosis.

BACKGROUND AND OBJECTIVES: Renal function is an important predictor of survival in cirrhosis and liver transplantation. GFR estimates using serum cystatin C (CysC) are proposed as better predictors of renal function than ones on the basis of serum creatinine (Cr). Our aims were: (1) evaluate correlations between serum CysC and different methods of creatinine measurements; (2) compare CysC and Cr GFR formulas with (51)Cr-EDTA; and (3) evaluate liver-related parameters potentially influencing GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 254 blood samples in 65 patients with cirrhosis correlating CysC with four Cr methods were used; another 74 patients comparing (51)Cr-EDTA GFR to Modification of Diet in Renal Disease and Larsson and Hoek formulas for CysC were also included. Agreement was assessed using Bland-Altman plots and concordance correlation coefficients. Multivariate linear regression analysis was used for GFR predictors. RESULTS: Serum CysC correlated modestly with O'Leary modified Jaffe, compensated kinetic Jaffe, enzymatic creatinine, and standard kinetic Jaffe 0.72/0.71/0.72/0.72 (all P < 0.001). Bland-Altman agreement with (51)Cr-EDTA GFR was poor; the best agreement was Modification of Diet in Renal Disease (concordance 0.61; 95% CI, 0.47 to 0.71); the worst agreement was the Hoek formula (concordance 0.46; 95% CI, 0.27 to 0.61). A new GFR formula including the Child-Pugh score improved the accuracy of Cr GFR formulas compared with (51)Cr-EDTA GFR. CONCLUSIONS: Estimated GFR in cirrhosis is not better with CysC formulas compared with creatinine ones: specific formulas may be necessary.

Proteomic analysis for developing new biomarkers of hepatocellular carcinoma.

AIM: To identify new markers of hepatocellular carcinoma (HCC) using a proteomic analysis. METHODS: Patients with liver cirrhosis of the three most frequent etiologies: hepatitis C virus, hepatitis B virus and alcoholic liver disease, were included in the study. The samples were analysed by 2D-electrophoresis in order to determine the differential protein expression. The proteins were separated according to the charge in immobilized pH 3-10 gradient strips and then by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins of interest were excised, digested with trypsin and the resulting peptides were separated and identified. RESULTS: Three differentially expressed apolipoproteins (Apo) were identified based on the protein profile using proteomic techniques: Apo-A1, Apo-A4 and Apo-E. Apo-A4 levels were significantly lower in HCC than in non-HCC patients regardless of etiology (P < 0.01). Multivariate logistic regression showed that Apo-A4 and Apo-A1 were the only independent factors related to HCC diagnosis (P < 0.05). The receiver operating characteristic (ROC) curve including both Apo-A4 and Apo-A1 showed an area under the ROC of 0.944 (P < 0.001), a sensitivity of 0.89 and a specificity of 0.81 for diagnosis of HCC. CONCLUSION: Apo-A4 and Apo-A1 may be used clinically as biomarkers of HCC with a high sensibility and specificity. These findings may provide additional insights into the mechanism of HCC development and progression.

Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis.

BACKGROUND & AIMS: A staged prognostic model of cirrhosis based on varices, ascites, and bleeding has been proposed. We analyzed data on infections in patients with cirrhosis to determine whether it is also a prognostic factor. METHODS: Studies were identified by MEDLINE, EMBASE, COCHRANE, and ISI Web of Science searches (1978-2009); search terms included sepsis, infection, mortality, and cirrhosis. Studies (n = 178) reporting more than 10 patients and mortality data were evaluated (225 cohorts, 11,987 patients). Mortality after 1, 3, and 12 months was compared with severity, site, microbial cause of infection, etiology of cirrhosis, and publication year. Pooled odds ratio of death was compared for infected versus noninfected groups (18 cohorts, 2317 patients). RESULTS: Overall median mortality of infected patients was 38%: 30.3% at 1 month and 63% at 12 months. Pooled odds ratio for death of infected versus noninfected patients was 3.75 (95% confidence interval, 2.12-4.23). In 101 studies that reported spontaneous bacterial peritonitis (7062 patients), the median mortality was 43.7%: 31.5% at 1 month and 66.2% at 12 months. In 30 studies that reported bacteremia (1437 patients), the median mortality rate was 42.2%. Mortality before 2000 was 47.7% and after 2000 was 32.3% (P = .023); mortality was reduced only at 30 days after spontaneous bacterial peritonitis (49% vs 31.5%; P = .005). CONCLUSIONS: In patients with cirrhosis, infections increase mortality 4-fold; 30% of patients die within 1 month after infection and another 30% die by 1 year. Prospective studies with prolonged follow-up evaluation and to evaluate preventative strategies are needed.

Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar carcinoma: a meta-analysis.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) is often the preferred local ablation therapy for hepatocellular carcinoma (HCC). Percutaneous ethanol injection (PEI) is less frequently used, and percutaneous acetic acid injection (PAI) has been mostly abandoned. Robust evidence showing benefit of one therapy versus another is lacking. Our aim was to evaluate the evidence comparing RFA, PEI and PAI using meta-analytical techniques. METHODS: Literature search was undertaken until December 2008 to identify comparative studies evaluating survival, recurrence, complete necrosis of tumour and complications. Only randomized clinical trials and quasi-randomized studies were included. Adjusted indirect comparisons were made when direct comparative studies were insufficient. RESULTS: Eight studies were identified: RFA vs. PEI (n=5), PAI vs. PEI (n=2) and RFA vs. PAI vs. PEI (n=1) including 1035 patients with nine comparisons. RFA was superior to PEI for survival (OR 0.52; 95% CI 0.35-0.78; p=0.001), complete necrosis of tumour and local recurrence. For tumours 2 cm RFA was not significantly better than PEI. PAI did not differ significantly from PEI for survival (OR 0.55; 95% CI 0.23-1.33; p=0.18), and local recurrence but required less sessions. PAI had similar outcomes, except local recurrence, to RFA in the direct and indirect comparison. CONCLUSIONS: RFA seems to be a superior ablative therapy than PEI for HCC, particularly for tumours >2 cm. PAI did not differ significantly from PEI for all the outcomes evaluated. RFA and PAI have similar survival rates. For tumours 2 cm outcome benefits comparing RFA and PEI are similar. PAI needs re-evaluation versus both PEI and RFA for tumours 2 cm.

Pros y contras de una lista de espera única para trasplante hepático / No disponible

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Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic venous pressure gradient.

UNLABELLED: Histopathological scoring of disease stage uses descriptive categories without measuring the amount of fibrosis. Collagen, the major component of fibrous tissue, can be quantified by computer-assisted digital image analysis (DIA) using histological sections. We determined relationships between DIA, Ishak stage, and hepatic venous pressure gradient (HVPG) reflecting severity of fibrosis. One hundred fifteen patients with hepatitis C virus (HCV) who had undergone transplantation had 250 consecutive transjugular liver biopsies combined with HVPG (median length, 22 mm; median total portal tracts, 12), evaluated using the Ishak system and stained with Sirus red for DIA. Liver collagen was expressed as collagen proportionate area (CPA). Median CPA was 6% (0.2-45), correlating with Ishak stage (stage 6 range, 13%-45%), and with HVPG (r = 0.62; P < 0.001). Median CPA was 4.1% when HVPG was less than 6 mm Hg and 13.8% when HVPG was 6 mm Hg or more (P < 0.0001) and 6% when HVPG was less than 10 mm Hg and 17.3% when HVPG was 10 mm Hg or higher (P < 0.0001). Only CPA, not Ishak stage/grade, was independently associated by logistic regression, with HVPG of 6 mm Hg or more [odds ratio, 1.206; 95% confidence interval (CI), 1.094-1.331; P < 0.001], or HVPG of 10 mm Hg or more (odds ratio, 1.105; 95% CI, 1.026-1.191; P = 0.009). CPA increased by 50% (3.6%) compared with 20% in HVPG (1 mm Hg) in 38 patients with repeated biopsies. CONCLUSION: CPA assessed by DIA correlated with Ishak stage scores and HVPG measured contemporaneously. CPA was a better histological correlate with HVPG than Ishak stage, had a greater numerical change when HVPG was low, and resulted in further quantitation of fibrosis in cirrhosis.

Impact of donor graft steatosis on overall outcome and viral recurrence after liver transplantation for hepatitis C virus cirrhosis.

The aim of this study was to determine the influence of donor graft steatosis on overall outcome, viral recurrence, and fibrosis progression in orthotopic liver transplantation (OLT) for hepatitis C virus (HCV) cirrhosis. One hundred twenty patients who underwent OLT for HCV cirrhosis between 1995 and 2005 were included in the study. Donor steatosis was categorized as absent (0%-10%; n = 40), mild (10%-30%; n = 32), moderate (30%-60%; n = 29), or severe (>60%; n = 19). A Cox multivariate analysis for marginal donor variables and a Model for End-Stage Liver Disease index were performed. Fibrosis evolution was analyzed in liver biopsies (fibrosis < 2 or > or =2) 3, 6, and 12 months post-OLT and in the late post-OLT period. Fifty-six grafts were lost (46%). The survival of the grafts was inversely proportional to donor liver steatosis: 82%, 72%, and 72% at 1, 2, and 3 years post-OLT in the absence of steatosis; 73%, 63%, and 58% with mild steatosis; 74%, 62%, and 43% with moderate steatosis; and 62%, 49%, and 42% with severe steatosis (P = 0.012). HCV recurrence was earlier and more frequent in recipients with steatosis > 30% (46% versus 32% at 3 months, P = 0.017; 58% versus 43% at 6 months, P = 0.020; 70% versus 56% at 12 months, P = 0.058; and 95% versus 69% at 3 years post-OLT, P = 0.0001). Graft survival was lower in alcoholic liver disease recipients versus HCV recipients when steatosis was >30% at 3, 6, and 12 months post-OLT (P = 0.042) but not when steatosis was <30% (P = 0.53). A higher fibrosis score was obtained 3 months post-OLT (P = 0.033), 6 months post-OLT (P = 0.306), 12 months post-OLT (P = 0.035), and in the late post-OLT period (P = 0.009). In conclusion, donor graft steatosis influences the outcome of OLT for HCV cirrhosis. HCV recurrence is more frequent and earlier in recipients of moderately and severely steatotic livers. Fibrosis evolution is higher when graft steatosis is >30%. OLT with >30% steatotic donor livers should be precluded in HCV recipients.

Surveillance and diagnosis of hepatocellular carcinoma in patients with cirrhosis.

Early identification of hepatocellular carcinoma (HCC) is more frequent because of surveillance programs for HCC worldwide. The optimal strategy of surveillance in cirrhosis is a current topical issue. In terms of diagnosis, recent advances in non-invasive imaging technology, including various techniques of harmonic ultrasound, new ultrasound contrast agents, multi-slice helical computed tomography and rapid high quality magnetic resonance, have all improved the accuracy of diagnosis. Consequently the role of liver biopsy in diagnosis of HCC has declined. The imaging diagnosis relies on the hallmark of arterial hypervascularity with portal venous washout. However, with recent advances in genomics and proteomics a great number of potential serum and tissue markers have been identified and are being developed as new candidate markers for both diagnosis and prognosis of hepatocellular carcinoma, and may increase the need for liver biopsy.

Evidence-based diagnosis and locoregional therapy for hepatocellular carcinoma.

Early identification of hepatocellular carcinoma (HCC) is crucial to improving the results of therapy and for patients to be eligible for liver transplantation. Recent advances in noninvasive imaging technology include various techniques of harmonic ultrasound, new ultrasound contrast agents, multislice helical computed tomography and rapid high-quality magnetic resonance. The imaging diagnosis relies on the hallmark of arterial hypervascularity with portal venous washout. Since the use of better radiological techniques has improved the accuracy of noninvasive diagnosis, the role of liver biopsy in the diagnosis of HCC has declined. With recent advances in genomics and proteomics, a great number of potential markers have been identified and developed as new candidate markers for HCC. Locoregional therapies currently constitute the best options for early nonsurgical treatment of HCC. Percutaneous ethanol injection shows similar results to resection surgery for single tumors less than 3 cm in diameter. Radiofrequency ablation is superior to percutaneous ethanol injection in terms of local recurrence. Transarterial chemoembolization is currently the most common approach for the management of HCC without curative options since it improves patient survival, but the optimal embolizing agent, length of interval between sessions and whether the chemotherapeutic agent has any effect have not yet been determined. Combining transarterial chemoembolization with antiangiogenic agents, as well as with other techniques, such as radiofrequency ablation, may improve the results. Injection of radioisotopes such as yttrium-90, via the hepatic artery, may be particularly useful in patients with portal vein thrombosis. Comparisons with other transarterial techniques are needed.

TACE versus TAE as therapy for hepatocellular carcinoma.

Transarterial chemoembolization (TACE) improves survival in cirrhotic patients with hepatocellular carcinoma (HCC). The optimal schedule, best anticancer agent and best technique are still unclear. TACE may not be better than transarterial embolization (TAE). HCC is very chemoresistant, thus embolization may be more important than chemotherapy. Lipiodol cannot be considered as an embolic agent and there are no data to show that it can release chemotherapeutic agents slowly. It can mask residual vascularity on CT imaging and its use is not recommended. Both TACE and TAE result in hypoxia, which stimulates angiogenesis, promoting tumor growth; thus combination of TACE with antiangiogenic agents may improve current results. To date, there is no evidence that TACE pre-liver transplantation or resection helps to expand current selection criteria for patients with HCC, nor results in less recurrence after surgery. Combination with other techniques, such as radiofrequency ablation and drugs, may enhance the effect of TACE. New trials are being conducted to clarify these issues.