Multicenter evaluation of the safety and efficacy of selective internal radiation therapy with yttrium-90 resin microspheres in Taiwan: data from the RESIN registry.

BACKGROUND AND AIM: The REgistry of Selective Internal radiation therapy in AsiaNs (RESIN) was a multicenter, single-arm, prospective, observational study of 90Y resin microspheres in patients with hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) from Taiwan. RESIN is the first real-life clinical study of this therapy in an Asian cohort. Study objectives were to evaluate the safety and efficacy of 90Y resin microspheres. METHODS: Adults with HCC or mCRC scheduled to receive SIRT with 90Y resin microspheres were included. Primary endpoints were best overall response rate (ORR), adverse events, and changes from baseline in liver function. Secondary efficacy endpoints included overall survival (OS). RESULTS: Of 107 enrolled patients, 83 had HCC, and 24 had mCRC. ORR was 55.41% (HCC) and 33.33% (mCRC). Of 58 HCC patients with 6-month post-SIRT data, 13.79% (n = 8) had resection, transplantation, transarterial chemoembolization, or radiofrequency ablation as the result of down-staging or down-sizing of their lesions. One hundred and ten treatment emergent adverse events (TEAEs) were reported in 51 patients, and five serious adverse events (SAEs) were reported in five patients. The most frequent TEAEs were abdominal pain, nausea and decreased appetite (HCC), and abdominal pain, decreased appetite, fatigue, and vomiting (mCRC). Two deaths due to SAEs (probably related to SIRT) were reported, both in patients with extensive HCC, active hepatitis infection, and other comorbidities. Median OS was 24.07 (HCC) and 12.66 (mCRC) months. CONCLUSIONS: Safety and efficacy outcomes with the routine use of SIRT with 90Y resin microspheres in Taiwan are consistent with published data.

Safety and long-term outcomes of early liver transplantation for pediatric methylmalonic acidemia patients.

BACKGROUND: LT is a treatment option for MMA patients, but renal function impairment is one of the long-term concerns. The aim of this study was to evaluate the outcomes of early LT in these patients. METHODS: A total of 11 MMA mut-type patients (including 10 mut0 cases and 1 mut-case) who received LT in our institute were reviewed. Their metabolic profiles were compared between the pre/post-transplant periods. Their immunosuppressant and renal function changes after transplantation were assessed. RESULTS: After a mean follow-up of 97.5 ± 38.4 months, there were two deaths, and the actual survival rate was 81.8%. Their metabolic profiles had improved (mean blood ammonia level 366.8 ± 105.5 vs. 53.1 ± 17.4 µg/dl, p < .001; C3/C2 ratio 2.68 ± 0.87 vs. 0.73 ± 0.22, p = .003; mean urine MMA level 920.5 ± 376.6 vs. 196.2 ± 85.4, p = .067), and hospital stays were decreased (78.8 ± 74.5 vs. 7.4 ± 7.0 days/year, p = .009) after transplantation. The mean age at transplant was 1.81 ± 2.02 years old, and nine of these patients received LT before the age of 1.5 years old (early LT). Under prospective immunosuppressant dose reduction, three of these early LT patients discontinued the drug and were sustained for more than 5 years. Most of the patients had a preserved renal function, and no patient is currently on dialysis. CONCLUSIONS: In addition to the improvement in the metabolic parameters, early LT in MMA patients may allow for a dose reduction of the immunosuppressant, and the patient's renal function could be preserved in the long term.

Dual hepatitis B and C-associated hepatocellular carcinoma: clinical characteristics, outcome, and prognostic role of albumin-bilirubin grade.

BACKGROUND: Albumin-bilirubin (ALBI) grade is used to evaluate the outcome of patients with hepatocellular carcinoma (HCC) which is often associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. This study aimed to investigate the clinical characteristics, outcome, and prognostic role of ALBI grade in dual HBV/HCV-related HCC. METHODS: A total 3341 HCC patients with viral etiology were prospectively enrolled and retrospectively analyzed. Multivariate Cox proportional hazards model was used to identify independent prognostic predictors. RESULTS: Of all patients, 2083 (62%), 1068 (32%), and 190 (6%) patients had HBV, HCV, and dual HBV/HCV infection, respectively. The mean age of HBV, HCV, and dual virus group was 60, 68, and 64 years (p < 0.001), respectively. There was no significant survival difference between HBV, HCV, and dual HBV/HCV-related HCC group (p = 0.712). Multivariate Cox analysis in dual HBV/HCV-related HCC showed that multiple tumors [hazard ratio (HR): 1.537, p = 0.044], tumor size >3 cm (HR 2.014, p = 0.044), total tumor volume (TTV) >50 cm3 (HR 3.050, p < 0.001), vascular invasion (HR 3.258, p < 0.001), performance status 2-4 (HR 2.232, p < 0.001), ALBI grade 2-3 (HR 2.177, p < 0.001), and BCLC stage B-D (HR 2.479, p < 0.001) were independent predictors of poor survival. CONCLUSIONS: Dual viral infection does not accelerate the development of HCC in HBV carriers. Patient survival is similar between dual HBV/HCV-related HCC and single HBV- or HCV-related HCC group. The ALBI grade is a robust prognostic model in dual virus-related HCC to discriminate patient long-term survival.

Easy albumin-bilirubin score as a new prognostic predictor in hepatocellular carcinoma.

BACKGROUND: Liver functional reserve is a major prognostic determinant in patients with hepatocellular carcinoma (HCC). The albumin-bilirubin (ALBI) score is an objective method to assess the severity of cirrhosis in this setting. However, calculation of the ALBI score is complex and difficult to access in clinical practice. Recently, the EZ (easy)-ALBI score was proposed as an alternative biomarker of liver injury. We aimed to evaluate the prognostic role of the EZ-ALBI score in HCC from early to advanced stages. METHODS: A total of 3794 newly diagnosed HCC patients were prospectively enrolled and retrospectively analyzed. Independent prognostic predictors were determined by using the multivariate Cox proportional hazards model. RESULTS: The EZ-ALBI score showed good correlation with the ALBI score (correlation coefficient, 0.965; p < 0.001). The correlation of the EZ-ALBI score was highly preserved in different Child-Turcotte-Pugh (CTP) classifications, treatment methods, and Barcelona Clinic Liver Cancer (BCLC) stages (correlation coefficients, 0.90-0.97). In the Cox multivariate analysis, age >65 years, male sex, serum α-fetoprotein >20 ng/ml, large or multiple tumors, total tumor volume >100 cm3 , vascular invasion or distant metastasis, ascites, poor performance status, EZ-ALBI grade 2 and 3, and noncurative treatments were independently associated with increased mortality (all p < 0.05). Moreover, EZ-ALBI grade can stratify long-term survival in patients with different CTP class, treatment strategy, and BCLC stage. CONCLUSIONS: The EZ-ALBI score is an easy and feasible method to evaluate liver functional reserve. As a new prognostic biomarker in HCC, the predictive power of the EZ-ALBI grade is independent across different cancer stages and treatments.

Albumin-bilirubin grade-based nomogram of the BCLC system for personalized prognostic prediction in hepatocellular carcinoma.

BACKGROUND & AIMS: The prognostic accuracy of individual hepatocellular carcinoma (HCC) patient in each Barcelona Clinic Liver Cancer (BCLC) stage is unclear. We aimed to develop and validate an albumin-bilirubin (ALBI) grade-based nomogram of BCLC to estimate survival for individual HCC patient. METHODS: Between 2002 and 2016, 3690 patients with newly diagnosed HCC were prospectively enrolled and retrospectively analysed. Patients were randomly split into derivation and validation cohort by 1:1 ratio. Multivariate Cox proportional hazards model was used to generate the nomogram from tumour burden, ALBI grade and performance status (PS). The concordance index and calibration plot were determined to evaluate the performance of this nomogram. RESULTS: Beta coefficients from the Cox model were used to assign nomogram points to different degrees of tumour burden, ALBI grade and PS. The scores of the nomogram ranged from 0 to 24, and were used to predict 3- and 5-year patient survival. The concordance index of this nomogram was 0.77 (95% confidence interval [CI]: 0.71-0.81) in the derivation cohort and 0.76 (95% CI: 0.71-0.81) in the validation cohort. The calibration plots to predict both 3- and 5-year survival rate well matched with the 45-degree ideal line for both cohorts, except for ALBI-based BCLC stage 0 in the validation cohort. CONCLUSIONS: The proposed ALBI-based nomogram of BCLC system is a simple and feasible strategy in the precision medicine era. Our data indicate it is a straightforward and user-friendly prognostic tool to estimate the survival of individual HCC patient except for very early stage patients.

A New Prognostic Model Based on Albumin-Bilirubin Grade for Hepatocellular Carcinoma Beyond the Milan Criteria.

BACKGROUND: The survival of patients with advanced hepatocellular carcinoma (HCC) is highly variable due to heterogeneous tumoral characteristics. We proposed and validated an albumin-bilirubin (ALBI)-based model for HCC beyond Milan criteria, the ALBI-HOME, for these patients. METHODS: A total of 2186 patients were enrolled and randomly assigned to the derivation cohort (n = 1093) and validation cohort (n = 1093). Multivariate Cox proportional hazards model was used to determine significant prognostic factors in the derivation cohort. The performance of ALBI-HOME was evaluated in the validation cohort. RESULTS: In the Cox model, six factors were identified as independent predictors of poor survival: ALBI grade 2 [hazard ratio (HR) 1.848, 95% confidence incidence (CI) 1.556-2.195, p < 0.001], ALBI grade 3 (HR 3.266, 95% CI 2.531-4.215, p < 0.001), serum AFP ≥ 100 ng/ml (HR 1.482, 95% CI 1.279-1.717, p < 0.001), total tumor volume ≥ 250 cm3 (HR 1.503, 95% CI 1.294-1.746, p < 0.001), ascites (HR 1.400, 95% CI 1.187-1.561, p < 0.001), performance status 0-1 (HR 1.756, 95% CI 1.485-2.076 p < 0.001), and vascular invasion or metastasis (HR 2.110, 95% CI 1.809-2.0, p < 0.001). The ALBI-HOME is based on these six parameters, and the score ranges from 0 to 7. This model was associated with the best prognostic ability among different HCC staging systems to predict survival in patients beyond Milan criteria; its ability remained consistently stable in different treatment subgroups and viral etiologies. CONCLUSIONS: The proposed ALBI-HOME is a simple and feasible predictive model for HCC beyond Milan criteria. It demonstrates superior prognostic performance among the currently used staging systems and may help identify at-risk patients to undergo more aggressive treatments.

Safe Strategy to Initiate Total Laparoscopic Donor Right Hepatectomy: A Stepwise Approach From a Laparoscopy-Assisted Method.

BACKGROUND: Total laparoscopic donor right hepatectomy (TLDRH) for adult living liver donors has been reported by a few experienced centers, but with limited cases, its safety and feasibility remain controversial. We report our experience initiating TLDRH using a stepwise approach to gradually convert laparoscopy-assisted donor right hepatectomy (LADRH) to TLDRH. METHODS: We retrospectively analyzed the data of 61 LADRHs, 56 conventional open donor right hepatectomies (CODRHs), and 3 TLDRHs performed between March 2014 and June 2018. RESULTS: There were no significant differences in perioperative outcomes between donors undergoing LADRH and CODRH, except for a slight elevations in the operative time (436.5 vs 392.9 min, p < 0.001) and the graft warm ischemic time (5.4 vs 4.0 min, p < 0.001) in the LADRH group. The recipients' posttransplant one-year survival rates in the LADRH and CODRH groups were also similar (93.2% and 94.6%, p = 0.384). For three donors in whom TLDRH was converted from LADRH in a stepwise manner, the average operative time and blood loss were 570 min and 316.7 ml, respectively. Donors were discharged on postoperative day 10 without any surgical complications. CONCLUSIONS: LADRH can be performed routinely on liver living donors. A stepwise approach could be adopted to "covert" suitable donors from LADRH to a total laparoscopic procedure to maximize donor safety. This strategy is reliable and could be reproduced in most LDLT centers.

Using nomogram of the Barcelona Clinic Liver Cancer system for treatment selection in patients with stage C hepatocellular carcinoma.

BACKGROUND: The nomogram of the Barcelona Clinic Liver Cancer (BCLC) for hepatocellular carcinoma (HCC) has been used for outcome prediction. Patients with BCLC stage C HCC often undergo anti-cancer therapy against current treatment guidelines in real world practice. We aimed to use the nomogram to provide guidance on treatment selection for BCLC stage C patients. METHODS: A total of 1317 patients with stage C HCC were retrospectively analyzed and divided into four groups by nomogram points. One-to-one matched pairs between patients receiving different treatments were generated by the propensity score with matching model within these groups. Survival analysis was performed by Kaplan-Meier method with log-rank test. RESULTS: Patients with higher nomogram points were more often treated with targeted or supportive therapies (p <  0.001). Patients receiving targeted or supportive therapies had a decreased survival compared to patients undergoing aggressive treatments (surgical resection, ablation, transarterial chemo-embolization or transplantation) across all four groups (p <  0.001). After matching for baseline differences in the propensity model, patients receiving different treatments had comparable age, gender, etiology of liver disease, tumor burden, severity of cirrhosis and performance status. Survival analyses were re-performed and disclosed that patients with nomogram points < 15 had better overall outcome after aggressive treatments (p <  0.05). For patients with nomogram points > 15, there was no significant difference in survival between patients receiving two different treatment strategies. CONCLUSIONS: The nomogram of BCLC system is a feasible tool to help stage C HCC patients to select primary anti-cancer treatment in pursuance of better overall survival.

ALBI and PALBI grade predict survival for HCC across treatment modalities and BCLC stages in the MELD Era.

BACKGROUND AND AIM: The severity of liver dysfunction in hepatocellular carcinoma (HCC) is often estimated with Child-Turcotte-Pugh (CTP) classification or model for end-stage liver disease (MELD) score. We aim to investigate the performance of albumin-bilirubin (ALBI) and platelet-albumin-bilirubin (PALBI) grade, which are recently reported to be simple and objective measurements for liver reserve in HCC. METHODS: Between 2002 and 2014, consecutive 3182 HCC patients were enrolled to follow up their survival. The area under receiver-operator-characteristic curve (AUC) was calculated to test the discriminatory powers over 1-year, 3-year, and 5-year survival. RESULTS: Significant survival differences were found across all ALBI and PALBI grades (both P < 0.001). The majority (73%) of patients were CTP class A. Within CTP class A, ALBI revealed two prognostic groups while PALBI segregated three prognostic groups. The PABLI grade also identified three different survival groups for patients undergoing resection, ablation, and chemoembolization. Both ALBI and PALBI grade were capable of discerning survival among different HCC stages. The PALBI grade had significantly higher AUC compared with CTP classification and ALBI grade at 1, 3, and 5 years. For CTP class A patients, the PALBI grade was also associated with significantly higher AUC compared with ALBI grade at 1-year and 3-year intervals. The MELD score has the lowest AUC compared with other systems. CONCLUSIONS: Both ALBI and PALBI grade are adequate models to assess liver dysfunction in HCC. The PALBI grade is consistently better in all patients, in patients with minimally decreased liver function, and in patients receiving different aggressive therapies.

Prognosis of hepatocellular carcinoma: Assessment of eleven staging systems.

BACKGROUND & AIMS: Multiple staging systems have been proposed for hepatocellular carcinoma (HCC). However there is no consensus regarding which system provides the best prognostic accuracy. We aimed to investigate the performance of 11 currently used HCC staging systems. METHODS: Between 2002 and 2013, a large prospective dataset of 3182 HCC patients were enrolled. The baseline characteristics and staging information were collected. Independent predictors of survival were identified. Homogeneity and corrected Akaike information criterion (AICc) were compared between each system. RESULTS: The median follow-up duration was 17months. Independent predictors of adverse outcome were serum albumin <3.5g/dl, bilirubin ⩾1mg/dl, creatinine ⩾1mg/dl, alpha-fetoprotein ⩾20ng/ml, alkaline phosphatase ⩾200IU/L, presence of ascites, multiple tumor nodules, maximal tumor size >5cm, presence of vascular invasion, presence of extrahepatic metastasis, and poor performance status (all p<0.001). Significant differences in survival were found across all stages of the 11 systems except between Hong Kong Liver Cancer stage IV and V, Japan Integrated Staging score 4 and 5, and Tokyo score 5 through 8. The Cancer of the Liver Italian Program (CLIP) score was associated with the highest homogeneity and lowest AICc value in the entire cohort. In subgroup analysis, the CLIP score was also superior in patients with hepatitis B- or hepatitis C-related HCC and in patients receiving curative or non-curative treatments. CONCLUSIONS: The CLIP staging system is stable and consistently the best prognostic model in all patients and in patients with different viral etiology and treatment strategy.

Surgical Resection Versus Radiofrequency Ablation for Single Hepatocellular Carcinoma ≤ 2  cm in a Propensity Score Model.

OBJECTIVES: To evaluate the efficacy of surgical resection (SR) and radiofrequency ablation (RFA) for single hepatocellular carcinoma (HCC) 2  cm or less. BACKGROUND: The optimal management for Barcelona Clínic Liver Cancer (BCLC) very early-stage HCC is undetermined. METHODS: Between 2002 and 2013, a total of 237 (SR, 109; RFA, 128) patients with BCLC very early-stage HCC were enrolled. Their overall survival (OS) and recurrence-free survival (RFS) were compared. Propensity score matching analysis identified 79 matched pairs of patients to compare outcomes. RESULTS: At baseline, patients with SR were younger and had larger tumors (both P < 0.05). The 5-year OS rates were 81% versus 76% (P = 0.136), whereas 5-year RFS rates were 49% versus 24% (P < 0.001) for SR and RFA groups, respectively. In the propensity model, the baseline variables were well balanced between 2 groups. Surgical resection was significantly associated with better OS and RFS compared with RFA; the 5-year OS rates were 80% versus 66% (P = 0.034), and 5-year RFS rates were 48% versus 18% (P < 0.001) for SR and RFA groups, respectively. The Cox proportional hazards model identified RFA as an independent predictor for mortality and tumor recurrence in the propensity model (hazard ratio, 2.120 and 2.421, respectively; both P < 0.05). Patients with recurrent HCC had inferior prognosis compared with patients without recurrence (P = 0.001). However, the survival after recurrence was similar between patients initially treated with SR or RFA (P = 0.415). CONCLUSIONS: Surgical resection provides better long-term OS and RFS compared with RFA in patients with BCLC very early-stage HCC. Surgical resection should be considered as the first-line treatment for these patients.

Surgical Resection is Better than Transarterial Chemoembolization for Patients with Hepatocellular Carcinoma Beyond the Milan Criteria: A Prognostic Nomogram Study.

BACKGROUND: The clinical outcomes in hepatocellular carcinoma (HCC) patients receiving surgical resection (SR) or transarterial chemoembolization (TACE) are diverse. This study aimed to develop a nomogram to predict individualized survival risk in patients with HCC beyond the Milan criteria undergoing aggressive treatments (SR and TACE). METHODS: A total of 1009 patients were enrolled in the study and randomly grouped into derivation (n = 505) and validation sets (n = 504). The multivariate Cox proportional hazards model was used to select significant prognostic predictors from the derivation set to generate the nomogram. The performance of the nomogram was evaluated by discrimination (concordance index) and calibration tests. RESULTS: Serum albumin <3.8 g/dL, α-fetoprotein ≥400 ng/mL, TACE, vascular invasion, multiple tumors, and tumor volume ≥200 cm(3) were associated with poor survival in the multivariate Cox model (all p < 0.05). A nomogram with a scale of 0-47 was developed with these six variables, and the predicted survival rates at 1 and 3 years were calculated. The derivation set with bootstrapping (B = 100) had a good concordance index of 0.694 [95% confidence interval (CI) 0.68-0.708]. Discrimination test in the validation set provided a concordance index of 0.71 (95 % CI 0.697-0.722), and the calibration plots well-matched the 45-degree line for 1- and 3-year survival prediction. The respective survival for patients undergoing SR or TACE could be predicted based on the nomogram across different risk scores. CONCLUSIONS: This easy-to-use nomogram may accurately predict survival at 1 and 3 years for individual HCC patients beyond the Milan criteria, and provide quantitative survival advantage of SR over TACE.

Nomogram of the Barcelona Clinic Liver Cancer system for individual prognostic prediction in hepatocellular carcinoma.

BACKGROUND & AIMS: The predictive accuracy of the Barcelona Clinic Liver Cancer (BCLC) staging system on a single patient is not clear. This study aimed to develop a nomogram to predict individualized survival of patients with hepatocellular carcinoma (HCC) based on the BCLC system. METHODS: A total of 3179 patients were randomly grouped into derivation (n = 2119) and validation (n = 1060) sets. The multivariate Cox proportional hazards model was used to generate the nomogram from tumour burden, cirrhosis and performance status (PS). The performance of the nomogram was evaluated by concordance indices and calibration tests. RESULTS: Beta coefficients from the Cox model were used to assign nomogram points to different degrees of tumour burden, Child-Turcotte-Pugh classification and PS. A nomogram with a scale of 0-26 was developed and the predicted survival rates at 3 and 5 years were calculated. The derivation set had a concordance index of 0.766 (95% confidence interval [CI]: 0.686-0.838); and the validation set showed a concordance index of 0.775 (95% CI: 0.607-0.909). The calibration plots were close to the 45-degree line for 3- and 5-year survival prediction of BCLC stages 0-C patients in both derivation and validation groups. For BCLC stage D patients, calibration plots in both groups showed deviation from the 45-degree line for 3- and 5-year prediction. CONCLUSIONS: This study provides quantitative evidence to support the prognostic ability of BCLC system. This straightforward and easy-to-use nomogram may accurately predict the survival at 3 and 5 years for individual HCC patient except for BCLC stage D patients.

Peroxisome Proliferator-Activated Receptor γ Expression Is Inversely Associated with Macroscopic Vascular Invasion in Human Hepatocellular Carcinoma.

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor that regulates cellular lipid and glucose metabolism and also plays an inhibitory role in various cancers. However, the role of PPARγ in hepatocellular carcinoma (HCC) remains controversial. This study aimed to investigate the prognostic value of PPARγ in HCC and its role in inhibiting tumor progression, namely, HCC cell growth, migration, and angiogenesis. Immunohistochemical PPARγ staining was examined in 83 HCC specimens to investigate the clinicopathological correlations between PPARγ expression and various parameters. The functional role of PPARγ was determined via PPARγ overexpression and knockdown in HCC cells. Patients with low HCC tissue PPARγ expression were significantly younger (p = 0.006), and exhibited more tumor numbers (p = 0.038), more macroscopic vascular invasion (MVI) (p = 0.008), and more advanced TNM (size of primary tumor, number of regional lymph nodes, and distant metastasis) stages at diagnosis (p = 0.013) than patients with high HCC tissue PPARγ expression. PPARγ knockdown increased HCC cell growth, migration, and angiogenesis, while PPARγ overexpression reduced HCC cell growth, migration, and angiogenesis. These results suggest that low PPARγ expression is an independent predictor of more MVI in HCC patients. PPARγ contributes to the suppression of HCC cell growth, migration, and angiogenesis. Therefore, PPARγ may be a therapeutic target in HCC patients.

Aggressive therapeutic strategies improve the survival of hepatocellular carcinoma patients with performance status 1 or 2: a propensity score analysis.

BACKGROUND: Targeted therapy or chemotherapy is suggested as standard treatment for hepatocellular carcinoma (HCC) patients with performance status (PS) 1-2 according to the Barcelona Clinic Liver Cancer (BCLC) system. The underlying rationales have not been fully studied. METHODS: This study enrolled 2,620 HCC patients. One-to-one matched pairs between HCC patients receiving aggressive anti-HCC treatments (resection, transplantation, ablation, and transarterial chemoembolization) and those receiving targeted therapy or chemotherapy or best supportive care were generated by using the propensity score with a matching model. Survival analysis was performed with the Kaplan-Meier method and the log-rank test. Mortality risk was calculated with the Cox proportional hazards model. RESULTS: Of 793 patients with PS 1-2, 64 % received aggressive anti-HCC treatments against the suggestion of the BCLC system. The patients receiving aggressive anti-HCC treatments had significantly milder cirrhosis, a smaller tumor burden, and better long-term survival than the patients undergoing targeted therapy or chemotherapy or best supportive care (all p < 0.05). With the use of propensity scores, 166 pairs of matched HCC patients with PS 1-2 were selected from different treatment groups. After matching, patients were comparable in age, gender, severity of cirrhosis, tumor burden, and prevalence of diabetes mellitus (all p > 0.05) at baseline. In the propensity score model, patients with PS 1-2 undergoing aggressive anti-HCC treatments had significantly better long-term survival (p < 0.0001). The adjusted hazard ratio of the choice for targeted therapy or chemotherapy or best supportive care to the choice for aggressive anti-HCC treatments was 2.028 (p < 0.0001). CONCLUSIONS: According to the findings, HCC patients with PS 1-2 should consider aggressive anticancer treatments if no contraindication is noted. Adjustment of the BCLC treatment allocation is needed to enhance its prognostic accuracy.

Impact of Steatosis on Prognosis of Patients with Early-Stage Hepatocellular Carcinoma After Hepatic Resection.

BACKGROUND: It is still unclear whether steatosis determines the prognosis of patients with hepatocellular carcinoma (HCC). This study aimed to compare the clinical manifestations and outcomes between early-stage HCC patients with and without steatosis after hepatic resection. METHODS: We enrolled 188 patients who underwent hepatic resection for HCC within the Milan criteria. After surgery, fibrosis, steatosis, lobular inflammation, portal inflammation, and ballooning in the background liver were assessed. Factors related to prognosis after surgery were analyzed by multivariate analysis. RESULTS: Seventy-four patients (39.4 %) had steatosis. Patients with steatosis had larger body mass index, higher fasting glucose levels, and higher rates of ballooning than those without steatosis. After a median follow-up period of 69.8 months, 73 patients died. The cumulative survival rates at 5 years were 57.8 and 75.6 % for patients with and without steatosis, respectively (p = 0.008). Multivariate analysis disclosed that an age of > 65 years [hazard ratio (HR) 1.996, p = 0.009], platelet count of <10(5)/mm(3) (HR 2.198, p = 0.005), indocyanine green retention rate at 15 min of >10 % (HR 2.037, p = 0.022), multinodularity (HR 2.389, p = 0.004), and steatosis (HR 1.773, p = 0.023) were independent risk factors associated with poor overall survival after resection. The impact of steatosis on postsurgical prognosis was more apparent in patients without cirrhosis. CONCLUSIONS: The presence of steatosis in the background liver was associated with a poor prognosis in early-stage HCC patients after hepatic resection, especially for noncirrhotic patients.

Surgical resection versus transarterial chemoembolization for BCLC stage C hepatocellular carcinoma.

BACKGROUND: Sorafenib is the only recommended treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC). We aimed to compare surgical resection (SR) and transarterial chemoembolization (TACE) for advanced (BCLC stage C) HCC patients. METHODS: A total of 264 and 389 advanced HCC patients received SR and TACE, respectively. Among them, 163 matched pairs of patients were identified from each treatment arm by propensity score matching analysis to compare long-term survival. RESULTS: Of all patients, the SR group had better liver functional reserve than the TACE group. In the matched propensity model, the baseline characteristics were similar between patients receiving SR and TACE. SR provided significantly better long-term survival than TACE in all patients and in patients selected in the propensity model (both P < 0.001). In the Cox proportional hazards model, patients receiving TACE had a 2.393-fold increased risk of mortality compared with patients receiving SR (95% confidence interval: 1.610-3.556, P < 0.001). CONCLUSIONS: SR provides significantly better long-term survival than TACE in patients with BCLC stage C HCC, and should be an integral part in the management of advanced HCC. Multidisciplinary approaches for these patients and further amendment to the BCLC classification scheme are required.

Active Treatments Prolong the Survival in Patients With Hepatocellular Carcinoma and Performance Status 3 or 4: A Propensity Score Analysis.

GOALS AND BACKGROUNDS: Best supportive care is suggested as the standard treatment for hepatocellular carcinoma (HCC) patients with performance status (PS) 3-4 by the Barcelona Clinic Liver Cancer (BCLC) system. To investigate the rationale of treatment allocation. STUDY: A total of 2660 HCC patients were reviewed. One-to-one matched pairs between PS 3 and 4 patients receiving supportive care and anti-HCC treatments were generated by using the propensity score with matching model. The survival analysis was performed with the Kaplan-Meier method and log-rank test. The hazard ratio was calculated with the Cox proportional hazards model. RESULTS: Among 328 patients with PS 3-4, 38% of patients received active anti-HCC treatments against the BCLC system. Compared with patients undergoing supportive care, patients receiving anti-HCC treatments more often had milder cirrhosis, smaller tumor burden, and lower serum α-fetoprotein levels (all P<0.05). Patients undergoing supportive care had significantly decreased survival (P<0.0001). With propensity scores, 101 pairs of similar HCC patients with PS 3-4 were selected from different treatment groups. They were comparable in age, sex, etiologies of liver disease, severity of cirrhosis, tumor burden, and prevalence of diabetes mellitus (all P>0.05) at baseline. In the matching model, patients with PS 3-4 undergoing supportive care had significantly shortened survival with an adjusted hazard ratio of 4.711 (confidence interval: 3.041-7.297, P<0.0001). CONCLUSIONS: Over one-third of patients with PS 3-4 receive active anti-HCC treatments against the BCLC allocation algorithm in this study. Active anticancer therapies rather than best supportive care should be performed if there is no apparent contraindication.

Radiofrequency ablation is better than surgical resection in patients with hepatocellular carcinoma within the Milan criteria and preserved liver function: a retrospective study using propensity score analyses.

GOALS/BACKGROUND: Radiofrequency ablation (RFA) and surgical resection (SR) are effective therapies for hepatocellular carcinoma (HCC) within the Milan criteria. We aimed to compare the treatment efficacy according to the liver functional reserve using propensity score analysis. STUDY: There were 330 and 369 HCC patients within the Milan criteria undergoing SR and RFA, respectively. A total of 147 and 48 pairs of patients with Child-Turcotte-Pugh (CTP) scores=5 and >5, respectively, were matched for analyses. RESULTS: Overall, the 3- and the 5-year survivals were 88% and 76% in the SR group and 80% and 66% in the RFA group, respectively (P=0.006). The SR group had significantly younger patients, a higher male-to-female ratio and hepatitis B infection rate, with a better liver functional reserve and performance status, and a larger tumor burden. In patients with a CTP score of 5, no survival difference was noted between the SR and the RFA groups (P=0.564). In patients with CTP score >5, the SR group had a better long-term survival than the RFA group (P=0.016). After propensity score analysis, the RFA group had a better long-term survival than the SR group in patients with CTP score=5 in the univariate (P=0.024) and the Cox proportional hazards models (hazard ratio: 0.47, P=0.031). Comparable survival results were noted between SR and RFA in patients with CTP score >5 (P=0.15). CONCLUSIONS: RFA is a safe procedure with better treatment efficacy than SR in patients with small HCC and a CTP score of 5, and provides effects comparable to SR in patients with CTP score >5. The baseline liver functional reserve may enhance treatment selection for outcome prediction.

Mitochondrial dysfunction represses HIF-1α protein synthesis through AMPK activation in human hepatoma HepG2 cells.

BACKGROUND: Hypoxia-inducible factor-1α (HIF-1α) is an important transcription factor that modulates cellular responses to hypoxia and also plays critical roles in cancer progression. Recently, somatic mutations and decreased copy number of mitochondrial DNA (mtDNA) were detected in hepatocellular carcinoma (HCC). These mutations were shown to have the potential to cause mitochondrial dysfunction. However, the effects and mechanisms of mitochondrial dysfunction on HIF-1α function are not fully understood. This study aims to explore the underlying mechanism by which mitochondrial dysfunction regulates HIF-1α expression. METHODS: Human hepatoma HepG2 cells were treated with various mitochondrial respiration inhibitors and an uncoupler, respectively, and the mRNA and protein expressions as well as transactivation activity of HIF-1α were determined. The role of AMP-activated protein kinase (AMPK) was further analyzed by compound C and AMPK knock-down. RESULTS: Treatments of mitochondrial inhibitors and an uncoupler respectively reduced both the protein level and transactivation activity of HIF-1α in HepG2 cells under normoxia or hypoxia. The mitochondrial dysfunction-repressed HIF-1α protein synthesis was associated with decreased phosphorylations of p70(S6K) and 4E-BP-1. Moreover, mitochondrial dysfunction decreased intracellular ATP content and elevated the phosphorylation of AMPK. Treatments with compound C, an AMPK inhibitor, and knock-down of AMPK partially rescued the mitochondrial dysfunction-repressed HIF-1α expression. CONCLUSIONS: Mitochondrial dysfunctions resulted in reduced HIF-1α protein synthesis through AMPK-dependent manner in HepG2 cells. GENERAL SIGNIFICANCE: Our results provided a mechanism for communication from mitochondria to the nucleus through AMPK-HIF-1α. Mitochondrial function is important for HIF-1α expression in cancer progression.