A prognostic model for patients with hepatocellular carcinoma within the Milan criteria undergoing non-transplant therapies, based on 1106 patients.

BACKGROUND: The Milan criteria are used to select candidates with small hepatocellular carcinoma (HCC) for liver transplantation. Due to severe shortage of donors, majority of patients within the Milan criteria need to seek alternative treatments. AIM: To propose a prognostic model for these patients undergoing non-transplant therapies. METHODS: A total of 1106 HCC patients, who were within the Milan criteria and received non-transplant therapies were retrospectively analysed. Patients were randomly assigned to the derivation and validation set according to treatments. A prognostic model was constructed from independent predictors of survival identified in the multivariate Cox model of the derivation set and was confirmed in the validation set. RESULTS: In the Cox model, serum bilirubin ≥1.5 mg/dL [risk ratio (RR): 1.525, P = 0.016], α-fetoprotein (AFP) ≥100 ng/mL (RR: 1.728, P < 0.001), mild ascites (RR: 1.705, P = 0.025) and moderate/severe ascites (RR: 4.163, P < 0.001) were independent predictors of poor survival in the derivation set (n = 553). A prognostic model with a total of 0-4 points was derived with the sum of three variables: 1 point each for bilirubin ≥1.5 mg/dL, AFP ≥100 ng/mL and mild ascites, and 2 points for moderate/severe ascites. This scoring system accurately predicted the survival in the validation set (n = 553; P < 0.001). The model consistently discriminated the survival in patients stratified by curative and noncurative treatments (both P values <0.001). CONCLUSION: The newly proposed prognostic scoring model, based on serum bilirubin and AFP level, and severity of ascites, is informative to predict the survival in non-transplant HCC patients within the Milan criteria.

Serum alpha-fetoprotein response can predict prognosis in hepatocellular carcinoma patients undergoing radiofrequency ablation therapy.

AIMS: To evaluate the clinical inference of serum alpha-fetoprotein (AFP) response in hepatocellular carcinoma (HCC) patients undergoing percutaneous radiofrequency ablation (RFA). MATERIALS AND METHODS: Three hundred and thirteen previously untreated HCC patients were enrolled in the study. The optimal AFP response was defined as >20% decrease from baseline after 1 month of RFA for those with a baseline AFP level of ≥100 ng/ml. The impact of AFP response on prognosis was analysed and prognostic factors were assessed. RESULTS: After a median follow-up of 26.7 ± 19.1 months, 49 patients died and 264 patients were alive. The cumulative 5 year survival rates were 75.3 and 57.4% in patients with an initial AFP of <100 ng/ml and ≥100 ng/ml, respectively (p = 0.003). In the 58 patients with a baseline AFP of ≥100 ng/ml and initial completed tumour necrosis after RFA, the cumulative 5 year survival rates were 62.4 and 25.7% in optimal and non-optimal AFP responders, respectively (p = 0.001). By multivariate analysis, the prothrombin time international normalized ratio >1.1 (p = 0.009), non-optimal AFP response (p = 0.023), and creatinine >1.5 mg/dl (p = 0.021) were independent risk factors predictive of poor overall survival. Besides, the cumulative 5 year recurrence rates were 83.4 and 100% in optimal and non-optimal AFP responders, respectively (p < 0.001). Multivariate analysis demonstrated platelet count ≤10(5)/mm(3) (p = 0.048), tumour size >2 cm (p = 0.027), and non-optimal AFP response (p < 0.001) were independent risk factors associated with tumour recurrence after RFA. CONCLUSIONS: Serum AFP response may be a useful marker for predicting prognosis in HCC patients undergoing RFA.

Comparison of the model for end-stage liver disease (MELD), MELD-Na and MELDNa for outcome prediction in patients with acute decompensated hepatitis.

BACKGROUND AND AIM: The model for end-stage liver disease (MELD) is used to predict the outcome of patients with cirrhosis. Incorporation of serum sodium (Na) into MELD may further increase its prognostic ability. Two Na-containing MELD models, MELD-Na and MELDNa, were proposed to enhance the prognostic ability. This study compared the predictive accuracy of these models for acute decompensated hepatitis. METHODS: We investigated the outcome of 182 patients with acute decompensated hepatitis. RESULTS: Twenty (11%) patients died at 3 months. The MELD-Na and MELDNa both had significantly higher area under the receiver operating characteristic curve (AUC) in comparison to MELD (MELD-Na: 0.908, MELDNa: 0.895, MELD: 0.823, p=0.004 and 0.001, respectively). Among 96 patients without specific antiviral treatment, the MELD-Na and MELDNa consistently had significantly higher AUC than the MELD (MELD-Na: 0.901, MELDNa: 0.882, MELD: 0.810, p=0.008 and 0.004, respectively). Three independent indicators, pre-existing cirrhosis (odds ratio [OR]: 5.67, 95% confidence interval [CI]: 1.72-18.7), serum albumin<3.7 g/dL (OR: 5.68, 95% CI: 1.18-27.03) and serum sodium (Na)<138 mequiv./L (OR: 10.0, 95% CI: 2.08-47.62), were associated with 3-month mortality. CONCLUSION: MELD-Na and MELDNa provide better prognostic accuracy than the MELD for patients with acute decompensated hepatitis. The adequacy of liver reserve determines the outcome of these patients.

The MELD-Na is an independent short- and long-term prognostic predictor for hepatocellular carcinoma: a prospective survey.

BACKGROUND AND AIM: Serum sodium has been suggested to incorporate into the model for end-stage liver disease to enhance its prognostic ability for cirrhosis. A mathematical equation based on model for end-stage liver disease and sodium, known as "MELD-Na", was developed for outcome prediction for cirrhosis. The severity of liver cirrhosis is a key component to predict survival in patients with hepatocellular carcinoma. This study investigated the prognostic role of MELD-Na for hepatocellular carcinoma. PATIENTS AND METHODS: A total of 535 unselected hepatocellular carcinoma patients were prospectively enrolled to evaluate the performance of MELD-Na. RESULTS: The MELD-Na was better than model for end-stage liver disease in predicting 6-month mortality by comparing the area under receiver operating characteristic curve (0.782 vs. 0.761, p=0.101). MELD-Na, but not model for end-stage liver disease, was an independent predictor associated with 6-month mortality in multivariate logistic regression analysis (odds ratio: 1.14, p=0.001). In the survival analysis, MELD-Na also independently predicted mortality, with an additional risk of 4.3% per unit increment of the score (p<0.001). Patients with MELD-Na scores between 10 and 20 and scores >20 had 2.1-fold (p<0.001) and 7.5-fold (p<0.001) risk of mortality, respectively, compared to patients with a score <10 in the Cox proportional hazard model. CONCLUSION: The MELD-Na score is a feasible and independent prognostic predictor for both short- and long-term outcome predictions in patients with hepatocellular carcinoma.

Evaluation of interleukin-6, interleukin-10 and human hepatocyte growth factor as tumor markers for hepatocellular carcinoma.

AIM: Serum alpha-fetoprotein (AFP) is the most important tumor marker for hepatocellular carcinoma (HCC). Previous reports indicated that HCC was also associated with increased levels of interleukin (IL)-6, IL-10 and hepatocyte growth factor (HGF). This study investigated the role of these cytokines as tumor markers for HCC. METHOD: A total of 128 adults were prospectively enrolled and categorized into four groups: normal subjects (n=29), chronic hepatitis B or C (n=50), non-HCC tumors (n=23) and HCC (n=26). Serum AFP, IL-6, IL-10 and HGF levels were determined in all subjects. RESULTS: The expression of IL-6 or IL-10 (> or =3 pg/ml), or high level of HGF (>1000 pg/ml) or AFP (>20 ng/ml) was observed in only 0-3% of normal subjects. Patients with HCC more frequently had higher IL-6 and IL-10 levels (p<0.05), whereas HGF levels in HCC patients were not significantly elevated compared to patients with chronic hepatitis or non-HCC tumors. Among patients with low (<20 ng/ml) AFP level, IL-6 or IL-10 expression was significantly associated with the existence of HCC (p<0.05). Patients with large (>5 cm) HCC more often had increased IL-6, IL-10 or AFP levels (p values all <0.05). CONCLUSIONS: Serum levels of IL-6 and IL-10 are frequently elevated in patients with HCC but not in benign liver disease or non-HCC tumors. IL-6 and IL-10 may help identify a subset of HCC patients with low AFP level, and may serve as complementary tumor markers in these patients.

Association of core promoter/precore mutations and viral load in e antigen-negative chronic hepatitis B patients.

Apart from core promoter A1762T/G1764A and precore G1896A mutations, other hepatitis B virus (HBV) mutants are detected in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). The aim of this study was to determine the effects of those mutants on clinical manifestation and viral loads of genotypes B and C HBV. Seventy-nine HBeAg-negative CHB patients with hepatitis flare were enrolled in this study and their HBV precore/core region were sequenced. Serial biochemical profiles and viral loads were assessed and compared. Fifty-three patients (67%) were infected by genotype B HBV and 26 (33%) were infected by genotype C HBV. The clinical manifestation and HBV viral loads were comparable between the two groups. However, genotype B was significantly associated with precore G1896A mutation (92.5%), and more mutations within nucleotide 1809-1817 were detected in patients infected by genotype B as compared with those infected by genotype C (18.9%vs 3.8%). Most of the cases had mutations at the -2, -3 or -5 position from the precore AUG initiation codon. Triple core promoter mutations T1753C/A1762T/G1764A [corrected] appeared to be linked to genotype C rather than genotype B HBV (19.2%vs 1.9%; P = 0.013). In multivariate analysis, the presence of either triple core promoter 1753/1762/1764 mutation or nucleotide 1809-1817 mutation was the only factor associated with lower HBV viral load (<70 Meq/mL) (odds ratio = 9.01; 95% CI 1.11-71.43; P = 0.04). In conclusion, minor HBV variants with mutations in the core promoter and precore region were detectable in genotypes B and C. Such HBV variants are genotype specific and related to viraemia levels.

Survival benefit of transcatheter arterial chemoembolization in patients with hepatocellular carcinoma larger than 10 cm in diameter.

BACKGROUND: The safety and survival benefit of transcatheter arterial chemoembolization for patients with huge hepatocellular carcinoma is uncertain. AIM: To evaluate the role of embolization in unresectable hepatocellular carcinomas larger than 10 cm. METHODS: Twenty-six consecutive patients who had an unresectable hepatocellular carcinoma larger than 10 cm and refused aggressive treatment, were enrolled as the control group. Another 31 patients matching with the control cases and undergoing embolization for huge unresectable hepatocellular carcinoma served as the embolization group. Survival between the two groups was compared. RESULTS: Two patients (7%) died from embolization-related complications. Patients in embolization group had longer survival than those in control group (median survival: 9.13 vs. 2.1 months). The 1-, 3- and 5-year survival rates in embolization group were 42%, 13% and 7% respectively. The 1- and 3-year survival rates for patients in control group were 8% and 0% respectively. In multivariate analysis, embolization and prothrombin ratio < or =1.2 were two independent factors associated with a better survival. CONCLUSIONS: Embolization-related mortality is low for huge hepatocellular carcinoma, and the technique provides survival benefit in patients with unresectable hepatocellular carcinomas larger than 10 cm in diameter.

The role of transcatheter arterial embolization for patients with unresectable hepatocellular carcinoma: a nationwide, multicentre study evaluated by cancer stage.

BACKGROUND: Transcatheter arterial embolization is a major palliative treatment for unresectable hepatocellular carcinoma, but the survival benefit of transcatheter arterial embolization is controversial. AIM: To evaluate the role of transcatheter arterial embolization in different stage of unresectable hepatocellular carcinoma and to select patients who can get the best benefit from the treatment. METHODS: From 1991 to 1995, 476 patients who had unresectable hepatocellular carcinoma from four medical centres in Taiwan were enrolled. Among them, 425 underwent transcatheter arterial embolization, and 51 received supportive treatment alone. The survivals between the two groups were compared. RESULTS: Among the 476 patients, transcatheter arterial embolization can significantly prolong survival. The 1-, 2-, and 5-year survival rates for patients who underwent transcatheter arterial embolization were 60.2%, 39.3%, and 11.5%; and the rates for patients who underwent supportive treatment were 37.3%, 17.6%, and 2%, respectively (P = 0.0002). The survival benefit of transcatheter arterial embolization was observed in patients between Cancer and the Liver Italian Program 0 and Cancer and the Liver Italian Program 4. In multivariate analysis, transcatheter arterial embolization, tumour size <5 cm and earlier Cancer and the Liver Italian Program stage were independent factors associated with a better survival. CONCLUSIONS: For patients who fulfilled the criteria of transcatheter arterial embolization, embolization can serve as a primary treatment for patients with unresectable hepatocellular carcinoma. The survival benefit of transcatheter arterial embolization is regardless of tumour stages.

Induction of complete tumor necrosis may reduce intrahepatic metastasis and prolong survival in patients with hepatocellular carcinoma undergoing locoregional therapy: a prospective study.

BACKGROUND: Transarterial chemoembolization (TACE) and percutaneous acetic acid injection (PAI) are effective locoregional therapies for hepatocellular carcinoma (HCC). This study aimed to investigate whether HCC patients who had initial complete response to these treatments had a subsequent lower risk of intrahepatic metastasis. PATIENTS AND METHODS: A total of 152 patients who underwent locoregional therapy (94 received PAI and 58 received both TACE and PAI) for HCC (tumor size < or =5 cm) were prospectively evaluated. RESULTS: In all, 60 (39%) patients had a complete tumor necrosis after treatment. The cumulative incidence of the development of intrahepatic metastasis was lower for patients with complete remission (P = 0.005) and for patients with smaller (< or =3 cm) tumor size (P = 0.083). Cox multivariate survival analysis showed that absence of complete remission [relative risk (RR) 2.7; 95% confidence interval (CI) 1.4-5.3; P = 0.003] was the only independent factor that predicted the occurrence of intrahepatic metastasis. Patients with complete remission had a significantly better long-term survival than those without (P = 0.002), and the occurrence of intrahepatic metastasis over time independently predicted a decreased survival (RR 3.2; 95% CI 2.0-6.1; P = 0.019). CONCLUSIONS: Induction of complete tumor necrosis in HCC patients undergoing locoregional therapy may decrease the risk of intrahepatic metastasis and improve survival.

Acute renal failure after transarterial chemoembolization for hepatocellular carcinoma: a retrospective study of the incidence, risk factors, clinical course and long-term outcome.

BACKGROUND: Transarterial chemoembolization is effective for hepatocellular carcinoma. Acute renal failure may occur after transarterial chemoembolization because of radiocontrast agent, but its clinical aspects are unknown. AIM: To investigate the incidence, risk factors and outcome of acute renal failure, defined as increase of serum creatinine > 1.5 mg/dL, after transarterial chemoembolization. METHODS: A total of 235 hepatocellular carcinoma patients with 843 transarterial chemoembolization treatment sessions were analysed. RESULTS: Acute renal failure developed in 56 (23.8%) patients and the estimated risk of developing acute renal failure was 6.6% in each treatment session. Comparison between the episodes of transarterial chemoembolization with and without acute renal failure by using the generalized estimating equation disclosed that Child-Pugh class B (odds ratio: 2.6, P = 0.007) and treatment session (odds ratio: 1.3; P < 0.0001) were independent risk factors of acute renal failure. Twenty-seven patients had prolonged renal function impairment. Multivariate analysis by generalized estimating equation showed that Child-Pugh class B (odds ratio: 4.3, P = 0.0004) and diabetes mellitus (odds ratio: 5.2, P < 0.0001) were linked with prolonged acute renal failure, which independently predicted a decreased survival (relative risk: 2.3, P = 0.002). CONCLUSIONS: Acute renal failure after transarterial chemoembolization appears to be dose-related and is associated with the severity of cirrhosis. Patients with diabetes mellitus or Child-Pugh class B more frequently develop prolonged acute renal failure, which in turn is a poor prognostic predictor.

Persistent retention of acetic acid is associated with complete tumour necrosis in patients with hepatocellular carcinoma undergoing percutaneous acetic acid injection.

BACKGROUND: Ultrasound (US)-guided percutaneous acetic acid injection therapy (PAIT) is effective for patients with hepatocellular carcinoma (HCC). This study aimed to determine the occurrence and predictive value of persistent intra-tumoral retention of acetic acid after PAIT. METHODS: We prospectively studied 60 (52 M, mean age 68 +/- 10 years) patients with 72 HCC nodules (45 < or = 3 cm) treated with PAIT. The presence of post-treatment persistent retention of acetic acid, defined as a homogeneous and highly hyperechoid mass in US appearance 3 days after completion of the treatment, was correlated with the treatment response. RESULTS: The mean size of the treated tumour was 2.9 +/- 1.0 cm (range 1.5-5 cm). Thirty (42%) HCC nodules showed complete tumour necrosis demonstrated by contrast-enhanced dynamic CT. Complete response was found in 22 (69%) of 32 nodules showing persistent intra-tumoral retention of acetic acid (P < 0.001). Small (< or = 3 cm) tumour size was also significantly associated with complete tumour necrosis (P = 0.001). There were no significant differences of the injection volume and treatment sessions between those with and without complete tumour necrosis in either small or large (> 3 cm) HCC (P > 0.1). Multivariate logistic regression analysis showed that persistent retention of acetic acid (odds ratio (OR) 10.4, 95% confidence interval (CI) 3.1-34.7; P < 0.001) and tumour size < or = 3 cm (OR 6.8, 95%, CI 1.8-25.8; P = 0.002) were independent factors predicting complete tumour necrosis. CONCLUSIONS: The presence of persistent retention of acetic acid is associated with a favourable response and may predict complete tumour necrosis after PAIT.

Reliability of contemporary radiology to measure tumour size of hepatocellular carcinoma in patients undergoing resection: limitations and clinical implications.

BACKGROUND: Preoperative radiology has been widely used to detect and measure hepatocellular carcinoma (HCC). However, its accuracy and reliability are unclear. This study aimed to assess the ability of current radiology to measure tumour size in patients undergoing resection. METHODS: We evaluated 212 HCC patients undergoing curative resection. Tumour size measured in the pathological examination was correlated with that obtained in preoperative ultrasound (US) and contrast-enhanced dynamic computed tomography (CT). Accuracy and association with tumour recurrence were investigated. RESULTS: The mean size of the tumour was 4.5 +/- 2.6 cm and was accurate in both US and CT in only 6 (3%) patients. Cirrhosis (P = 0.015), absence of tumour stain (P = 0.002) and small (< or = 4 cm) tumour (P < 0.001) were the significant factors associated with size deviation using both US and CT. Ninety-four (44%) patients developed tumour recurrence within 17 +/- 11 months of resection. Recurrence rate was 52%, 52% and 67% in patients with underestimation in US (relative risk [RR]: 2.0, 95% confidence interval [CI]: 1.2-3.4, P = 0.01), CT (RR: 2.1, 95% CI: 1.1-4, P = 0.022) and both modalities (RR: 2.5, 95% CI: 1.4-4.2, P = 0.001), respectively, compared to 30% recurrence in patients with accurate estimation of tumour size. CONCLUSION: The accuracy of radiology in measuring tumour size was poor, and may lead to inappropriate treatment. The finding that underestimation of tumour size was associated with a higher tumour recurrence rate is consistent with the hypothesis that HCC may recur from pre-existing tumour foci which could not be identified from the current imaging modalities.

Sequential transarterial chemoembolization and percutaneous acetic acid injection therapy versus repeated percutaneous acetic acid injection for unresectable hepatocellular carcinoma: a prospective study.

BACKGROUND: Transarterial chemoembolization (TACE) and percutaneous acetic acid injection (PAI) are effective treatments for hepatocellular carcinoma (HCC). We have conducted a prospective study to compare the efficacy of sequential TACE and PAI (TACE-PAI) versus repeated PAI therapy for HCC. PATIENTS AND METHODS: A total of 108 HCC patients with tumor size

Comparison of percutaneous acetic acid injection and percutaneous ethanol injection for hepatocellular carcinoma in cirrhotic patients: a prospective study.

BACKGROUND: Ultrasound-guided percutaneous ethanol injection (PEI) and percutaneous acetic acid injection (PAI) are effective in the treatment of hepatocellular carcinoma (HCC). We conducted a prospective study to compare the therapeutic efficacy of both these methods. METHODS: Sixty-three patients were treated by PAI using 50% acetic acid and 62 by PEI using pure ethanol. There were no significant baseline differences in age, sex, Child-Pugh class, tumour size and number, or other clinico-biochemical parameters between the two groups. RESULTS: During a follow-up period of 24 +/- 9 (range 6-38) months, 19 (30%) of the PAI group and 21 (34%) of the PEI group died (P = 0.704). The 1- and 3-year survival rates were 84% and 51% for the PAI group and 81% and 46% for the PEI group (P = 0.651). The corresponding tumour recurrence rates were 51% and 74% for the PAI group, and 54% and 64% for the PEI group (P = 0.787). The treatment sessions were 3.9 +/- 1.6 and 6.2 +/- 2.3 for the PAI and PEI groups, respectively, in each treatment cycle (P = 0.008). A multivariate analysis using the Cox regression model revealed that ascites (relative risk (RR) 3.1, 95% confidence interval (CI) 1.5-6.3, P = 0.002), large (>3 cm) or multinodular HCCs (RR 2.4, 95% CI 1.1-5.4, P = 0.04), and development of tumour recurrence (RR 7.0, 95% CI 3.1-16.0, P < 0.001) were independent, poor prognostic factors in both groups. CONCLUSIONS: PAI and PEI are equally effective in the treatment of HCC. PAI has the advantage of fewer treatment sessions in each treatment course. Careful pretreatment patient selection may improve survival.

Analysis of clinical, biochemical and viral factors associated with early relapse after lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B patients in Taiwan.

The efficacy of lamivudine for HBeAg-negative chronic hepatitis B (CHB) Chinese patients has not been fully investigated. The role of the Hepatitis B virus (HBV) genotype on the treatment effect of lamivudine is controversial. Thirty-two consecutive patients with HBeAg-negative CHB were enrolled. All patients were treated with lamivudine 100 mg once daily of 7-12 months duration. The mean total period of follow-up since entry for all patients was 24 +/- 3.5 months. HBV genotypes were classified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and verified by sequencing. Precore (G1896A) and basic core promoter (BCP, A1762T & G1764A) mutations were determined by PCR and direct sequencing. Twenty-one (65.6%) patients were infected by genotype B and, 11 (34.4%) by genotype C. G1896A was predominant in genotype B infected patients (95.2%vs 63.6%, P = 0.037). At the end of treatment, 31 (96.8%) and 14 (43.8%) patients achieved biochemical and virological responses, respectively. The biochemical and virological response rates were 40.6 and 0% at 12 months after treatment. Eighteen (56.3%) patients had biochemical relapse within 12 months after withdrawal of lamivudine. By multivariate analysis, the pretreatment serum level of HBV DNA >/=12 Meq/mL was the only factor associated with early biochemical relapse (Odds ratio = 9.333, 95% CI = 1.497 approximately 58.197, P = 0.017). In conclusion, the virological effect of lamivudine for HBeAg-negative CHB is transient. Most patients had biochemical relapse within 12 months after lamivudine treatment regardless of HBV genotype. A high pretreatment viral load is the determinant for early biochemical relapse.

Hepatitis B virus X mutants derived from human hepatocellular carcinoma retain the ability to abrogate p53-induced apoptosis.

Chronic hepatitis B virus (HBV) infection and the integration of its X gene (HBx) are closely associated with the development of hepatocellular carcinoma (HCC). The integrated HBx frequently is truncated or contains point mutations. Previous studies indicated that these HBx mutants have a diminished co-transactivational activity. We have compared the effects of wild-type (wt) HBx and its naturally occurring mutants derived from human HCCs on transcriptional co-transactivation, apoptosis and interactive effects with p53. We demonstrated that overexpression of mutant, but not wt HBx, is defective in transcriptional co-transactivation of the NF-kappaB-driven luciferase reporter. By using a microinjection technique, the HBx mutants were shown to have an attenuated pro-apoptotic activity. This deficiency may be attributed to multiple mutations in the co-transactivation domain of HBx, that leads to decreased stability of the translated product. However, wt or mutant HBx bind to p53 in vitro and retain their ability to block p53-mediated apoptosis in vivo, which has been implicated as its major tumor suppressor function. The abrogation of p53-mediated apoptosis by integrated HBx mutants may provide a selective clonal advantage for preneoplastic or neoplastic hepatocytes and contribute to hepatocellular carcinogenesis.