High-Intensity Focused Ultrasound Ablation Combined With Pharmacogenomic-Guided Chemotherapy for Advanced Pancreatic Cancer: Initial Experience.

OBJECTIVE: To investigate the safety and efficacy of high-intensity focused ultrasound (HIFU) ablation combined with pharmacogenomic-guided chemotherapy in treating patients with advanced pancreatic cancer (PC). METHODS: Thirty-one patients with unresectable PC (stage III 17, stage IV 14) were enrolled in this study. The patients were divided into group A (pharmacogenomic-guided chemotherapy following HIFU treatment, n = 13) and group B (traditional chemotherapy following HIFU treatment, n = 18). Contrast-enhanced computed tomography and magnetic resonance imaging were used to evaluate tumor response. Pain intensity was assessed using the numerical rating scale. The Kaplan-Meier method and log-rank test were used to analyze survival. RESULTS: The mean pain intensity score in 18 patients decreased from 6.6 ± 2.2 before HIFU to 3.3 ± 1.0 after HIFU (p = 0.000). The mean duration of pain relief was 5.2 ± 3.2 mo in group A and 2.4 ± 1.3 mo in group B (p = 0.026). There was no significant difference of the non-perfused volume ratio (83.5% ± 22.3% in group A and 85.3% ± 16.8% in group B) between the two groups. The median survival time was 14 mo in group A and 5 mo in group B. The 6 and 12-mo survival rates were 74.1% and 59.3% in group A, and 32.4% and 19.4% in group B, respectively. The difference in survival between the two groups was significant (p = 0.04). No severe complications (≥grade 3) related to HIFU were observed. Bone marrow depression was the main adverse reaction related to chemotherapy, with grade 3 bone marrow depression observed 2 (15.4%) patients in group A and 7 (38.9%) patients in group B. CONCLUSION: HIFU combined with pharmacogenomic-guided chemotherapy is safe and effective in treating patients with advanced PC. It provides better clinical outcomes in pain relief, quality of life and survival benefits for patients with advanced PC compared to HIFU combined with traditional chemotherapy. This combined approach may have the potential to become an important supplement to the treatment of advanced PC.

Evaluating the long-term survival benefits of high intensity focused ultrasound ablation for hepatocellular carcinoma with portal vein tumor thrombus: a single center retrospective study.

AIMS: To evaluate the long-term survival benefits of high intensity focused ultrasound (HIFU) ablation in patients with hepatocellular carcinoma (HCC) combined with portal vein tumor thrombus (PVTT). METHODS: The data of patients with HCC-PVTT treated with HIFU from January 2014 to December 2019 were retrospectively analyzed. All patients received HIFU ablation for both PVTT and liver tumor in one session. Perioperative adverse events (AEs) were recorded, and follow-up was performed postoperatively. The Kaplan-Meier method was used for survival analysis. RESULTS: Median follow-up was 13.75 ± 1.31 months. A total of 144 patients (male/female: 122/22, age: 54.15 ± 11.84 years old) were included in the study. A total of 267 liver tumors (tumor number: 1.87 ± 1.65, range 1-10) were treated with HIFU. The mean ± SD diameter of viable liver tumors was 100.98 ± 61.65 mm. The reported postoperative AEs of HIFU were skin edema (93.75%), local pain (69.44%) and fever (7.64%). There was no liver failure, gastrointestinal bleeding or perioperative death. The median overall survival (OS) time was 14 months, while the cumulative survival rates of 0.5, 1, 2 and 3 years were 79.0%, 58.6%, 33.3% and 5.9%, respectively. The median OS of PVTT types I, II and III was 22, 13 and 14 months, respectively, and the difference was not statistically significant (p > 0.05). CONCLUSION: HIFU is a minimally invasive method for HCC-PVTT with fewer complications, which could prolong the OS. Patients with PVTT type III could benefit more from HIFU, compared to types I and II.

Feasibility of High-Intensity Focused Ultrasound for Hepatocellular Carcinoma after Stereotactic Body Radiation Therapy: Initial Experience.

The purpose of this initial clinical observation was to investigate the safety and effect of high-intensity focused ultrasound (HIFU) for patients with hepatocellular carcinoma (HCC) after stereotactic body radiation therapy (SBRT). Twenty patients who had been treated with SBRT, with 24 local residuals, received HIFU ablation. The changes of periphery blood cell count and serum biochemistry were observed before HIFU and 1 week after. Contrast-enhanced magnetic resonance imaging before HIFU and 2 weeks after was performed to assess the effect of HIFU. All patients received follow-up. The mean ± standard deviation follow-up time was 19.3 ± 18.0 mo. The median survival time and 1-y survival rate were 21 mo and 76.2%. Seventeen residual lesions (70.8%) received complete ablation and seven received partial ablation, with a mean ablation ratio of 75.8% ± 18.2%. No significant differences were found in periphery blood cell counts or serum biochemistry 1 week after HIFU compared with before HIFU. No severe adverse reactions related to HIFU were observed. Thus, we believe that HIFU can safely and effectively ablate residual HCC after SBRT, which may be a feasible option for patients with HCC who have local residuals after SBRT.

Effects of high-intensity focused ultrasound treatment on peripancreatic arterial and venous blood vessels in pancreatic cancer.

The present study aimed to evaluate the safety of high-intensity focused ultrasound (HIFU) treatment on peripancreatic arterial and venous blood vessels in patients with pancreatic cancer. This trial included 15 patients with pancreatic cancer (9 females and 6 males; age, 39-81 years; median age, 62 years). All patients underwent preoperative computed tomography (CT) or magnetic resonance imaging (MRI) and color Doppler flow imaging (CDFI) to assess the vascular hemodynamics of peripancreatic arterial and venous blood vessels pre-treatment. These patients were re-examined within 1 week post-HIFU treatment. Then, vascular adverse events were observed and followed up clinically. Prior to HIFU treatment, vessel involvement was recorded in 13 patients, including tumor lesions invading 19 veins and 14 arteries, which refers to the growth of pancreatic tumor lesions surrounding blood vessels, or tumor growth into blood vessels. In addition, 9 veins and 13 arteries were <1 cm from the lesions. The hemodynamic parameters of peripancreatic vessels were measured using CDFI, including mean blood flow velocity, peak systolic blood flow velocity, vascular resistance index, vascular pulsatility index, vascular diameter, vascular blood flow and other indicators, to assess vascular perfusion in CT/MRI. There were no significant differences in preoperative and postoperative hemodynamic data (P>0.05). Overall, HIFU demonstrated no negative effects on peripancreatic arterial and venous blood vessels in patients with pancreatic cancer, even with tumor lesions wrapped in blood vessels. In addition, no complications of vascular stenosis and vascular adverse events were observed in the present study.

Efficacy and safety of high-intensity focused ultrasound ablation for hepatocellular carcinoma by changing the acoustic environment: microbubble contrast agent (SonoVue) and transcatheter arterial chemoembolization.

OBJECTIVE: To compare efficacy and safety of microbubble contrast agent (SonoVue) and transcatheter arterial chemoembolization (TACE) in combination with high-intensity focused ultrasound (HIFU) for treatment of patients with hepatocellular carcinoma (HCC). METHODS: According to our inclusion criteria, we retrospectively reviewed 52 patients with HCCs, and divided them into SonoVue group and TACE group. Tumors were examined by enhanced magnetic resonance imaging. Change of lesions, alpha-fetoprotein values, hepatic and renal function were measured pre- and postoperatively. Then, adverse events were observed and clinical follow-up was performed. RESULTS: Clinical efficacy and the majority of treatment parameters were similar, except for time and energy required for the first massive grey-scale changes in SonoVue group, which were significantly lower than those in TACE group (p < .05). For adverse events, only rate of fever (3.85%) in SonoVue group was significantly lower than that in TACE group (50.00%, p < .05). The 'diagnosis and treatment cycle' in SonoVue group (11.5 ± 2.9) was remarkably shorter than TACE group (22.7 ± 6.3, p < .05). Energy efficiency factor was positively correlated with distance from the deepest layer of lesion to the hepatic capsule or to the abdominal wall in SonoVue group, while that was negatively correlated with iodized oil deposition in TACE group. CONCLUSION: Using microbubble (SonoVue) in HIFU procedure has a similar therapeutic effect compared with TACE, and does not increase the risk of treatment. It might present a new strategy in clinical treatment, especially for patients with a smaller diameter of HCC.

High-intensity focused ultrasound ablation for treatment of hepatocellular carcinoma and hypersplenism: preliminary study.

The purpose of this work was to preliminarily investigate the efficacy and safety of high-intensity focused ultrasound treatment of hepatocellular carcinoma and hypersplenism. Nine patients with hepatocellular carcinoma complicated by hypersplenism (5 male and 4 female; median age, 56 years; range, 51-66 years) were treated with ultrasound-guided high-intensity focused ultrasound. Complications were recorded. Laboratory examination and magnetic resonance imaging were used to evaluate the efficacy. After high-intensity focused ultrasound treatment, mean spleen ablation ± SD of 28.76% ± 6.1% was discovered; meanwhile, the white blood cell count, platelet count, and liver function of the patients were substantially improved during the follow-up period. In addition, symptoms such as epistaxis and gingival bleeding were ameliorated or even eliminated, and the quality of life was improved. Follow-up imaging showed a nonperfused volume in the spleen and an absence of a tumor blood supply at the treated lesions in the liver. For the first time to our knowledge, high-intensity focused ultrasound ablation was used to treat hepatocellular carcinoma complicated by hypersplenism. High-intensity focused ultrasound may be an effective and safe alternative for treatment of hepatocellular carcinoma complicated by hypersplenism, but further studies are necessary to clarify the mechanisms.

Experimental studies and clinical experiences on treatment of secondary hypersplenism with extracorporeal high-intensity focused ultrasound.

The aim of this study is to investigate the efficacy and safety of extracorporeal high-intensity focused ultrasound (HIFU) in treatment of hypersplenism. Fifteen adult dogs, weighing 13-18 kg were divided into three groups: sham group, SVL group undergoing splenic vein ligation (SVL) after laparotomy, and SVL + HIFU group receiving SVL followed by extracorporeal HIFU. Pathologic and hematologic analyses were performed. We also reviewed the clinical data of 19 patients with secondary hypersplenism caused by liver cirrhosis or hepatocellular carcinoma who underwent extracorporeal HIFU. Extracorporeal HIFU significantly diminished the volume of the spleen of animals, coupled with occurrence of coagulation necrosis and fibrosis in the target area. Both platelet and red blood cell counts were significantly restored by HIFU intervention. Similarly, HIFU treatment improved the hematologic parameters in patients with hypersplenism, and no major complications were encountered. Extracorporeal HIFU intervention is effective and safe in managing secondary hypersplenism.

High-intensity focused ultrasound combined with transarterial chemoembolization for unresectable hepatocellular carcinoma: long-term follow-up and clinical analysis.

OBJECTIVE: High-intensity focused ultrasound (HIFU) combined with transarterial chemoembolization (TACE) has been used to treat unresectable HCC, but its long-term effects and major prognostic factors remain to be determined. The purpose of this study was to assess its long-term effects and find major prognostic factors to help us select eligible patients in the future. METHODS: 73 patients with unresectable HCC received follow-up after HIFU+TACE. The variables of sex, age, AFP level, liver function, tumor location, tumor number, tumor size, TNM staging (5th edition), TNM staging (6th edition), portal vein invasion, ultrasonic pathway of HIFU, TACE session and ablation response were evaluated by univariate analysis. Those variables with significant difference were assessed by multivariate analysis. RESULTS: The mean follow-up time was 11.7±11.1 months (range, 1-60 months). The median survival time and overall survival rates of 1, 2, 3-year were 12 months, 49.1%, 18.8%, 8.4%, respectively. 45.2% patients achieved complete ablation. At the end of follow-up, 51 patients (69.9%) died from tumor progression (27 patients), liver function failure (18 patients), hemorrhage of upper digestive tract (3 patients) and infection (3 patients). 1 with liver abscess, 2 with serious skin burns and 2 with rib fracture were observed after HIFU. On univariate analysis, age (P=0.017), tumor size (P=0.000), tumor number (P=0.039), the 5th edition of TNM staging (P=0.023), portal vein invasion (P=0.02) and ablation response (P=0.000) had significant difference. On multivariate analysis, ablation response (P=0.001) and tumor size (P=0.013) were major prognostic factors. CONCLUSION: HIFU combined with TACE is a safe method with a low rate of severe complications. As major prognostic factors, ablation response and tumor size may help us predict the survival and select eligible patients clinically.

Feasibility of US-guided high-intensity focused ultrasound treatment in patients with advanced pancreatic cancer: initial experience.

The study was approved by the university ethics committee, and informed consent was obtained from all patients. The purpose of this study was to prospectively evaluate ultrasonographically guided high-intensity focused ultrasound in the treatment of patients with advanced-stage pancreatic cancer. Eight patients underwent high-intensity focused ultrasound ablation, and laboratory and radiologic examinations were performed after intervention. Changes in symptoms and survival time were noted at follow-up. No complications were observed, and preexisting severe back pain disappeared after intervention. Follow-up images revealed an absence of tumor blood supply and shrinkage of the ablated tumor. Four patients died, and four patients were alive at the time of this writing, with a median survival time of 11.25 months. The authors conclude that high-intensity focused ultrasound ablation is safe and feasible in the treatment of advanced pancreatic cancer.

Extracorporeal high intensity focused ultrasound treatment for patients with breast cancer.

PURPOSE: To investigate the safety, efficacy and feasibility of using high-intensity focused ultrasound (HIFU) as a non-invasive treatment for patients with breast cancer. PATIENTS AND METHODS: Twenty-two patients with breast cancer were enrolled into this non-randomized prospective trial. Disease TNM stage was classified as stage I in 4 patients, stage II(A) in 9 patients, stage II(B) in 8 patients, and stage IV in 1 patient. Tumor size ranged from 2 to 4.8 cm in diameter (mean 3.4 cm). All patients received chemotherapy, radiation and tamoxifen, following HIFU for the primary lesions. Outcome measures included radiological and pathologic assessment of the treated tumor, cosmesis, and local recurrence. A cumulative survival rate is calculated by using the Kaplan-Meier method. RESULTS: No severe complications were encountered after HIFU. Post-operative imaging demonstrated positive response and regression of all treated lesions. Follow-up biopsy revealed coagulation necrosis of target tumor and subsequent replacement by fibroblastic tissue. After a median follow-up of 54.8 months, 1 patient died, 1 was lost to follow-up, and 20 were still alive. Two of 22 patients developed local recurrence. Five-year disease-free survival and recurrence-free survival were 95% and 89%, respectively. Cosmetic result was judged as good to excellent in 94% of patients. CONCLUSIONS: HIFU treatment is safe, effective, and feasible for patients with breast cancer. But, large-scale, multiple-center clinical trials will be needed to determine the future role of this novel modality.

Advanced hepatocellular carcinoma: treatment with high-intensity focused ultrasound ablation combined with transcatheter arterial embolization.

PURPOSE: To evaluate ultrasonographically (US)-guided high-intensity focused ultrasound ablation combined with transcatheter arterial chemoembolization (TACE) in the treatment of stage IVA hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. From November 1998 to May 2000, 50 consecutive patients with stage IVA HCC (TNM classification, T4N0-1M0) were alternately enrolled in one of two treatment groups: group 1 (n = 26), in which TACE was performed alone, and group 2 (n = 24), in which transcutaneous ablation of HCC with high-intensity focused ultrasound was performed 2-4 weeks after TACE. The tumors were 4-14 cm in diameter (mean, 10.5 cm). Immediate therapeutic effects were assessed at follow-up with Doppler US and computed tomography or magnetic resonance imaging. All patients were followed up for 3-24 months (mean, 8 months) to observe long-term therapeutic effects and complications in both groups. Tumor reduction rates, median survival time, and cumulative survival rates in both groups were calculated by using the unpaired Student t test and Kaplan-Meier method. RESULTS: No severe complication was observed after focused ultrasound ablation, and no unexpected side effects were noted after TACE. Follow-up images showed absence or reduction of blood supply in the lesions after focused ultrasound ablation when compared with blood supply after TACE alone. The median survival time was 11.3 months in group 2 and 4.0 months in group 1 (P = .004). The 6-month survival rate was 80.4%-85.4% in group 2 and 13.2% in group 1 (P = .002), and the 1-year survival rate was 42.9% and 0%, respectively. Median reductions in tumor size as a percentage of initial tumor volume at 1, 3, 6, and 12 months after treatment, respectively, were 28.6%, 35.0%, 50.0%, and 50.0% in group 2 and 4.8%, 7.7%, 10.0%, and 0% in group 1 (P < .01). CONCLUSION: The combination of high-intensity focused ultrasound ablation and TACE is a promising approach in patients with advanced-stage HCC, but large-scale randomized clinical trials are necessary for confirmation.

Activated anti-tumor immunity in cancer patients after high intensity focused ultrasound ablation.

T cell-mediated immune responses represent the main cellular antitumor immunity in cancer patients. Recent studies have shown that that both surgical procedure and radiation therapy could cause the functional suppression of lymphocyte-mediated cellular immunity. The purpose of current study is to evaluate whether high intensity focused ultrasound (HIFU) might change a systemic antitumor immunity, particularly T lymphocyte-mediated immunity in cancer patients. A total of 16 patients with solid malignancies were treated with HIFU. Among them, six patients had osteosarcoma (Enneking stage, II(B)4, III(B) 2), five had hepatocellular carcinoma (TNM stage, III 3, IV 2), and five had renal cell carcinoma (TNM stage, III 2, IV 3). Using flow cytometry technique, T lymphocyte and subset, B lymphocyte and natural killer cell (NK) in the peripheral blood were measured in these patients on the day before HIFU and 7 to 10 d after HIFU. The statistical significance of any observed difference is evaluated by Student's t-test. The results showed a significance increase in the population of CD4(+) lymphocytes (p < 0.01) and the ratio of CD4(+) /CD8(+) (p < 0.05) in the circulation of cancer patients after HIFU treatment. The abnormal levels of CD3(+) lymphocytes returned toward the normal range in two patients, CD4(+)/CD8(+) ratio in 3, CD19(+) lymphocytes in one and cytotoxic NK in one, respectively, in comparison to control values. It is concluded that HIFU could enhance a systemic antitumor cellular immunity in addition to local tumor destruction in patients with solid malignancies.

Extracorporeal high intensity focused ultrasound ablation in the treatment of patients with large hepatocellular carcinoma.

BACKGROUND: High intensity focused ultrasound (HIFU) is a noninvasive treatment modality that induces complete coagulative necrosis of a deep tumor through the intact skin. The current study was conducted to determine the safety, efficacy, and feasibility of extracorporeal HIFU in the treatment of patients with hepatocellular carcinoma (HCC). METHODS: A total of 55 patients with HCC with cirrhosis were enrolled in this prospective, nonrandomized clinical trial. Among them, 51 patients had unresectable HCC. Tumor size ranged from 4 to 14 cm in diameter with mean diameter of 8.14 cm. According to tumor, node, metastasis (TNM) classification, 15 patients corresponded to stage II, 16 to stage IIIA, and 24 to IIIC. All patients had HIFU, and the median number of HIFU session was 1.69. Safety and efficacy of HIFU were assessed in this trial. RESULTS: No severe side effect was observed in the patients treated with HIFU. Follow-up imaging showed an absence of tumor vascular supply and the shrinkage of treated lesions. Serum alpha-fetoprotein returned to normal level in 34% of patients. The overall survival rates at 6, 12, and 18 months were 86.1%, 61.5%, and 35.3%, respectively. The survival rates were significantly higher in patients in stage II than those in stage IIIA (P = .0132) and in stage IIIC (P = .0265). CONCLUSION: As a noninvasive therapy, HIFU appears to be effective, safe, and feasible in the treatment of patients with HCC. It may play an important role in the ablation of large tumors.

Circulating tumor cells in patients with solid malignancy treated by high-intensity focused ultrasound.

The theoretical possibility that exposure of a solid malignancy to high-intensity focused ultrasound (US), or HIFU, could lead to an increased rate of metastasis still remains. Using reverse transcriptase polymerase chain reaction (RT-PCR), the potential risk of hematogenous dissemination was assessed in HIFU-treated patients with solid malignancy. RT-PCR can demonstrate the presence or absence of specific RNA fragments. On the day before HIFU ablation, 5-mL peripheral blood samples were collected, and again 5 to 7 days after HIFU, from 26 enrolled patients (hepatocellular carcinoma, HCC: 10; osteosarcoma: 16). Total RNA was isolated and RT-PCR was performed to analyze the mRNA expression of (alpha-fetoprotein (AFP) and bone-specific alkaline phosphatase (BALP) genes. Positive AFP mRNA expression was preoperatively detected in 8 of 10 patients with HCC. In the postoperative specimens, positive expression was also detected in 8 of 10 patients. In 2 patients, circulating tumor cells were found preoperatively, but not postoperatively. Conversely, 2 patients with no circulating tumor cells preoperatively were found to have circulating tumor cells after HIFU. Of 16 osteosarcoma patients, 12 patients had circulating tumor cells and 4 had none. After HIFU treatment, 2 of the 12 patients had converted from presence to absence of circulating cells and the remaining 4 patients remained negative. It is concluded that patients undergoing complete HIFU ablation may demonstrate conversion from presence to absence of circulating tumor-specific marker mRNA, and that HIFU would not enhance the potential risk of metastasis in patients with malignant diseases.

Extracorporeal focused ultrasound surgery for treatment of human solid carcinomas: early Chinese clinical experience.

The objective of this article is to introduce the early Chinese clinical experience of using extracorporeal focused ultrasound (US) surgery (FUS) for the treatment of solid tumors. From December 1997 to October 2001, a total of 1038 patients with solid tumors underwent FUS ablation in 10 Chinese hospitals. The tumors included primary and metastatic liver cancer, malignant bone tumors, breast cancer, soft tissue sarcomas, kidney cancer, pancreatic cancer, abdominal and pelvic malignant tumors, uterine myoma, benign breast tumors, hepatic hemangioma and other solid tumors. In this article, pathologic changes in tumors treated with FUS, real-time diagnostic imaging for targeting, monitoring and assessment of results by follow-up images are presented. Early clinical results and complications of the technique are also reported.

Changes in biologic characteristics of breast cancer treated with high-intensity focused ultrasound.

Proliferation, invasion, immortalization and metastasis are the main malignant characteristics of cancer. Previous studies have shown that high-intensity focused ultrasound (US), or HIFU, can induce irreversible damage both to breast cancer cells and to tumor blood vessels. However, light microscopy alone may not always show this clearly. In this study, molecular biologic techniques were used to examine any changes in molecular markers associated with malignant behavior after exposure to HIFU. A total of 48 women with breast cancer were randomized to a control group (mastectomy) and a HIFU group (HIFU followed by mastectomy). Immunohistochemical staining, messenger RNA (mRNA) in situ hybridization and telomere-repeat amplification protocol-enzyme-linked immunosorbent assay (TRAP-ELISA) techniques were used to detect tumor expression of proliferating cell nuclear antigen (PCNA), cell adhesion molecule CD44v6, matrix metalloproteinase-9 (MMP-9), erbB2 mRNA, and to measure telomerase activity in both groups. The results demonstrated that there were significant alterations in expression of PCNA, CD44v6, MMP-9, erbB2 mRNA, and a dramatic decrease in telomerase activity in the HIFU group. It is concluded that malignant tumor characteristics are arrested by HIFU, and that biologic factors are potential markers for assessing HIFU efficacy.

[High intensity focused ultrasound therapy combined with transcatheter arterial chemoembolization for advanced hepatocellular carcinoma].

OBJECTIVE: To study high intensity focused ultrasound (HIFU) therapy combined with transcatheter arterial chemoembolization (TACE) in the treatment of patients with advanced hepatocellular carcinoma (HCC). METHODS: Fifty patients with unresectable HCC (TNM stage IV) were randomized into a TACE (T) group and a TACE plus HIFU (T + H) group. Twenty-six patients underwent TACE alone, and 24 HIFU ablation 2 - 3 weeks after TACE. The mean follow-up time for all patients was 8.16 +/- 2.79 months (range 3 to 24 months). The median survival, 6-month-, 1-year survival rates and average survival of patients who died were calculated by Kaplan-Meier method and Fisher exact test. RESULTS: The median survival time, 6-month and 1-year survival rates were 11.3 months, 80.4 - 85.4% and 42.9% in T + H group, in contrast to 4 months, 13.2% and 0% in T group with significant differences (P < 0.01). The average survival time of patients who died was 10.21 +/- 4.12 months in T + H group, as compared with 4.35 +/- 2.39 months in T group also with significant differences (P < 0.01). CONCLUSION: High intensity focused ultrasound therapy (HIFU) combined with transcatheter arterial chemoembolization (TACE), being better than TACE alone, may become one of the most effective treatments for patients with unresectable HCC.