Serum folate concentrations at diagnosis are associated with hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort study.

Existing data on folate status and hepatocellular carcinoma (HCC) prognosis are scarce. We prospectively examined whether serum folate concentrations at diagnosis were associated with liver cancer-specific survival (LCSS) and overall survival (OS) among 982 patients with newly diagnosed, previously untreated HCC, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study between September 2013 and February 2017. Serum folate concentrations were measured using chemiluminescent microparticle immunoassay. Cox proportional hazards models were performed to estimate hazard ratios (HR) and 95 % CI by sex-specific quartile of serum folate. Compared with patients in the third quartile of serum folate, patients in the lowest quartile had significantly inferior LCSS (HR = 1·48; 95 % CI 1·05, 2·09) and OS (HR = 1·43; 95 % CI 1·03, 1·99) after adjustment for non-clinical and clinical prognostic factors. The associations were not significantly modified by sex, age at diagnosis, alcohol drinking status and Barcelona Clinic Liver Cancer (BCLC) stage. However, there were statistically significant interactions on both multiplicative and additive scale between serum folate and C-reactive protein (CRP) levels or smoking status and the associations of lower serum folate with worse LCSS and OS were only evident among patients with CRP > 3·0 mg/l or current smokers. An inverse association with LCSS were also observed among patients with liver damage score ≥3. These results suggest that lower serum folate concentrations at diagnosis are independently associated with worse HCC survival, most prominently among patients with systemic inflammation and current smokers. A future trial of folate supplementation seems to be promising in HCC patients with lower folate status.

Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma.

Sorafenib is the most recommended first-line systemic therapy for advanced hepatocellular carcinoma (HCC). Yet there is no clinically applied biomarker for predicting sorafenib response. We have demonstrated that a vascular pattern, named VETC (Vessels that Encapsulate Tumor Clusters), facilitates the release of whole tumor clusters into the bloodstream; VETC-mediated metastasis relies on vascular pattern, but not on migration and invasion of cancer cells. In this study, we aimed to explore whether vascular pattern could predict sorafenib benefit. Two cohorts of patients were recruited from four academic hospitals. The survival benefit of sorafenib treatment for patients with or without the VETC pattern (VETC+ /VETC- ) was investigated. Kaplan-Meier analyses revealed that sorafenib treatment significantly reduced death risk and prolonged overall survival (OS; in cohort 1/2, P = 0.004/0.005; hazard ratio [HR] = 0.567/0.408) and postrecurrence survival (PRS; in cohort 1/2, P = 0.001/0.002; HR = 0.506/0.384) in VETC+ patients. However, sorafenib therapy was not beneficial for VETC- patients (OS in cohort 1/2, P = 0.204/0.549; HR = 0.761/1.221; PRS in cohort 1/2, P = 0.121/0.644; HR = 0.728/1.161). Univariate and multivariate analyses confirmed that sorafenib treatment significantly improved OS/PRS in VETC+ , but not VETC- , patients. Further mechanistic investigations showed that VETC+ and VETC- HCCs displayed similar levels of light chain 3 (LC3) and phosphorylated extracellular signal-regulated kinase (ERK) in tumor tissues (pERK) or endothelial cells (EC-pERK), and greater sorafenib benefit was consistently observed in VETC+ HCC patients than VETC- irrespective of levels of pERK/EC-pERK/LC3, suggesting that the different sorafenib benefit between VETC+ and VETC- HCCs may not result from activation of Raf/mitogen-activated protein kinase kinase (MEK)/ERK and vascular endothelial growth factor (VEGF)A/VEGF receptor 2 (VEGFR2)/ERK signaling or induction of autophagy. Conclusion: Sorafenib is effective in prolonging the survival of VETC+ , but not VETC- , patients. VETC pattern may act as a predictor of sorafenib benefit for HCC.

Multimodality Treatment for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Large-Scale, Multicenter, Propensity Mathching Score Analysis.

The optimal treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remains controversial. We aimed to investigate the best treatment for patients with HCC with PVTT. From January 2002 to January 2014, the data from all consecutive patients with HCC with PVTT who underwent surgical treatment (ST),TACE,TACE combined with sorafenib (TACE-Sor), or TACE combined with radiotherapy (TACE-RT) in the 4 largest tertiary hospitals in China were analyzed retrospectively. The patients were divided into 3 subtypes according to the extent of PVTT in the portal vein (type I-III). The primary endpoint was overall survival (OS). A total of 1580 patients with HCC with PVTT were included in the study. The median survival times (MST) for ST (n = 745) for type I, II, and III patients (95% CI) were 15.9 (13.3-18.5), 12.5 (10.7-14.3), and 6.0 (4.3-7.7) months, respectively. The corresponding figures for patients after TACE (n = 604) were 9.3 (5.6-12.9), 4.9 (4.1-5.7), and 4.0 (3.1-4.9), respectively; for patients after TACE-Sor (n = 113) 12.0 (6.6-17.4), 8.9 (6.7-11.1), and 7.0 (3.0-10.9), respectively; and for patients after TACE-RT (n = 118) 12.2 (0-24.7), 10.6 (6.8-14.5), and 8.9 (5.2-12.6), respectively. Comparison among the different treatments for the 3 subtypes of PVTT patients after propensity score (PS) matching showed the effectiveness of ST to be the best for type I and type II PVTT patients, and TACE-RT was most beneficial for type III patients. Treatment was an independent risk factor of OS. ST was the best treatment for type I and II PVTT patients with Child-Pugh A and selected B liver function. TACE-RT should be given to type III PVTT patients.

Long-term therapy with sorafenib is associated with pancreatic atrophy.

BACKGROUND: Although the short-term adverse effects of sorafenib are well known, few data exist on long-term toxicity. The objective of the present study was to investigate the prevalence of pancreatic atrophy among a cohort of patients with hepatocellular carcinoma (HCC) who were treated with sorafenib for ≥2 y. METHODS: Between March 2007 and December 2013, 31 patients with HCC who were treated with sorafenib for ≥2 y were identified. The effect of pancreatic atrophy and enhancement on incidence of adverse events, tumor response, and overall survival (OS) were assessed. RESULTS: Thirty-one patients with HCC were treated with sorafenib for ≥2 y and met inclusion criteria; 11 patients (35.5%) were Barcelona-clinic liver cancer stage B, whereas 20 patients (64.5%) were Barcelona-clinic liver cancer stage C. Median duration of treatment with sorafenib was 35.2 mo. Pancreatic atrophy and a decrease in pancreatic enhancement occurred in 24 patients (77.4%) and 15 patients (48.4%), respectively. On the basis of the modified response evaluation criteria in solid tumors, four patients (12.9%) had a complete response, 10 patients (32.3%) had a partial response, and 17 patients (54.8%) had stable disease. Patients treated with sorafenib with pancreatic atrophy had a median OS of 49.4 mo (95% confidence interval, 41.2-57.5 mo) compared with 31.2 mo (95% confidence interval, 25.7-36.7 mo) among patients who did not develop pancreatic atrophy (P = 0.009). In contrast, survival was not associated with decreased versus normal enhancement of the pancreas (OS, 47.7 mo versus 41.7 mo, respectively; P = 0.739). CONCLUSIONS: Pancreatic atrophy occurred in many HCC patients after 2 y of treatment with sorafenib. Patients who experienced pancreatic atrophy had a better tumor response and OS.

Roles played by chemolipiodolization and embolization in chemoembolization for hepatocellular carcinoma: single-blind, randomized trial.

BACKGROUND: The aim of our study was to compare the efficacy and safety of: 1) transarterial chemolipiodolization with gelatin sponge embolization vs chemolipiodolization without embolization, and 2) chemolipiodolization with triple chemotherapeutic agents vs epirubicin alone. METHODS: A single-blind, three parallel arm, randomized trial was conducted at three clinical centers with patients with biopsy-confirmed unresectable hepatocellular carcinoma. Arm 1 received triple-drug chemolipiodolization and sponge embolization, whereas Arm 2 received triple-drug chemolipiodolization only. Patients in arm 3 were treated with single-drug chemolipiodolization and sponge embolization. We compared overall survival and time to progression. Event-time distributions were estimated by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: From July 2007 to November 2009, 365 patients (Arm 1: n = 122; Arm 2: n = 121; Arm 3: n = 122) were recruited. The median tumor size was 10.9cm (range = 7-22cm), and 34.5% had macrovascular invasion. The median survivals and time to progression in Arm 1, Arm 2, and Arm 3 were 10.5 and 3.6 months, 10.1 and 3.1 months, and 5.9 and 3.1 months, respectively. Survival was statistically significantly better in Arm 1 than in Arm 3 (P < .001), whereas there was no statistically significant difference between Arm 1 and Arm 2 (P = .20). Objective response rates were 45.9%, 29.7%, and 18.9% for Arm 1, Arm 2, and Arm 3, respectively. CONCLUSIONS: Chemolipiodolization played an important role in transarterial chemoembolization, and the choice of chemotherapy regimen may largely affect survival outcomes. However, the removal of embolization from chemoembolization might not statistically significantly decrease survival.

Hepatic resection versus transarterial lipiodol chemoembolization as the initial treatment for large, multiple, and resectable hepatocellular carcinomas: a prospective nonrandomized analysis.

PURPOSE: To compare the survival outcomes between hepatic resection and transarterial lipiodol chemoembolization (TACE) used as the initial treatment in patients with large (≥5 cm), multiple, and resectable hepatocellular carcinomas. MATERIALS AND METHODS: This study had local ethical committee approval; all patients gave written informed consent. Between January 2004 and December 2006, 168 consecutive patients were prospectively studied. As an initial treatment, 85 patients underwent hepatic resection and 83 underwent TACE. Of the 29 of 83 patients in whom there was a good response to TACE, 13 underwent subsequent hepatic resection. The remaining 16 patients, who refused hepatic resection, underwent TACE and local ablation. Repeated TACE was performed in patients with stable disease or progressive disease after initial TACE. The differences in survival between groups and subgroups were calculated with the Kaplan-Meier method. Univariate and multivariate analyses were performed to clarify the prognostic factors for survival. RESULTS: The 1-, 3-, and 5-year overall survival rates for the initial hepatic resection group and the initial TACE group were 70.6%, 35.3%, 23.9% and 67.2%, 26.0%, 18.9%, respectively (P = .26). Complication rates were significantly higher in the initial hepatic resection group than in the initial TACE group (P < .01). The 1-, 3-, and 5-year overall survival rates in patients who underwent initial TACE and subsequent hepatic resection were 92.3%, 67.3%, and 50.5%, respectively, which were significantly higher than rates in patients treated with initial hepatic resection (P = .04) but were not significantly higher than in patients who responded well to TACE but refused hepatic resection (P = .07). Tumor size was the independent risk factor for survival. CONCLUSION: TACE might be a better initial treatment in patients with large, multiple, and resectable hepatocellular carcinomas; hepatic resection should be recommended to patients who respond well to TACE.

[Clinical observation of sorafenib monotherapy in Chinese patients with advanced hepatocellular carcinoma].

OBJECTIVE: To observe the efficacy and safety of sorafenib monotherapy in Chinese patients with advanced hepatocellular carcinoma (HCC). METHODS: Thirty-eight patients with advanced HCC of Child-Pugh status A or B were included in this study. Patients received orally administered sorafenib at a dose of 400 mg twice a day on a continuous schedule. Adverse events were documented. The efficacy and safety were evaluated every four to six weeks. RESULTS: During the treatment, partial response (PR) was observed in 1 patient (2.6%), minor response (MR) in 5 (13.2%), stable disease (SD) in 16 (42.1%), and progressive disease (PD) in 16 (42.1%), respectively. The median oral administration time of sorafenib was 180 days (range, 15-550 d), and the mean overall survival was 370 days (range, 42-562 days). The median response duration was 169 days (range, 42-426 days). The mean overall survival of 22 patients with controlled disease (PR + MR + SD) was 428 days (95% CI 330-526 days). The most frequent adverse events were dermal reaction (27 cases, 71.1%), gastrointestinal reaction (25 cases, 65.8%), and constitutional symptoms (14 cases, 36.8%). Most of the drug related adverse events were mild and easily to manage and reversible. CONCLUSION: Sorafenib monotherapy is effective and tolerable in a part of Chinese patients with advanced hepatocellular carcinoma and liver function of Child-Pugh A or B, and may prolong their survival.

[Treatment of hepatic functional reserve injury after TACE in hepatocellular carcinoma with Chinese herbal medicines].

BACKGROUND & OBJECTIVE: Transcatheter arterial chemoembolization (TACE) has been proved to injure hepatic functional reserve. The current study was designed to evaluate the effect of Chinese herbal medicines in treatment of hepatic functional reserve injury after TACE. METHODS: Sixty-one advanced hepatocellular carcinoma patients were divided into two groups: groups A (Western medicine combined with Chinese herbal medicine group, n = 30) and group B (Western medicine group, n = 31). Western medicines were used to protect hepatic function and alleviate TACE syndrome in both group A and group B. Invigorating the spleen and activating blood circulation Chinese herbal medicines were added only in group A before and after TACE. Retention rate of Indocyanine green at 15 minutes (ICGR15) was measured in both group A and group B before 1st, 2nd TACE and one month after 2nd TACE respectively. RESULTS: Hepatic functional reserve before 1st TACE was 11.18% +/- 7.30% in group A and 11.83 +/- 7.18% in group B, (P > 0.05). Hepatic functional reserve before 2nd TACE was 11.69% +/- 5.13% in group A and 16.64 +/- 10.15% in group B, (P < 0.05). Hepatic functional reserve one month after 2nd TACE was 11.53% +/- 5.30% in group A and 19.80 +/- 11.26% in group B, (P < 0.05). CONCLUSIONS: Invigorating the spleen and activating blood circulation Chinese herbal medicine can prevent hepatic functional reserve injury after TACE.

High-dose iodized oil transcatheter arterial chemoembolization for patients with large hepatocellular carcinoma.

AIM: To conduct a randomized trial to evaluate the role of using high-dose iodized oil transcatheter arterial chemoembolization (TACE) in the treatment of large hepatocellular carcinoma (HCC). METHODS: From January 1993 to June 1998, 473 patients with unresectable hepatocellular carcinoma were divided into two groups: 216 patients in group A received more than 20 mL iodized oil during the first TACE treatment; 257 patients in group B received 5-15 mL iodized oil in the same way. The Child's classification and ICG-R15 for evaluating the liver function of the patients were done before the treatment. During the TACE procedure the catheters were inserted into the target artery selectively and the tumor vessels were demonstrated with contrast medium in the hepatic angiography.The anticancer drugs mixed with iodized oil (Lipiodol) were Epirubicin and Mitomycin. In group A, 112 cases received 20-29 mL Lipiodol in the first procedure, 85 cases 30-39 mL, 19 cases more than 40 mL. The largest dose was 53 mL and the average dose was 28.3 mL. In group B, 119 cases received 5-10 mL Lipiodol,138 cases received 11-15 mL and the average dose was 11.8 mL. RESULTS: High-dose Lipiodol chemoembolization had tolerable side effects and a little hurt to the liver function in the patients with Child's A or ICG-R15<20. But the patients with child's B or ICG-R15>20 had higher risk of liver failure after high-dose TACE. More type I and type II in CT scan after 4 weeks of TACE were seen in the patients of group A than those in the patients of group B (P<0.01). The resection rate and complete tumor necrosis rate of group A were higher than those of group B (P<0.05). The 1-,2-, 3-year survival rates of group A patients with Child's A were 79.2 , 51.8 and 34.9 , respectively, better than those of group A (P<0.001). CONCLUSION: High-dose Lipiodol can result in more complete tumor necrosis by blocking both arteries and small portal vein of the tumor. High-dose TACE for treatment of large and hypervascular hepatocellular carcinoma is practically acceptable with the better effect than the routine dose. For the patients with large and hypervascular tumor of Child grade A liver function or ICG-R15 less than 20%, oily chemoembolization with 20-40 mL Lipiodol is recommended.