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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

The purpose of this study was to assess the effectiveness of high-intensity focused ultrasound (HIFU) combined with transarterial chemoembolization (TACE) in treating pediatric hepatoblastoma. Twelve patients with initially unresectable hepatoblastoma were enrolled in the study. All patients received chemotherapy, TACE, and HIFU ablation. Follow-up materials were obtained in all patients. The tumor response, survival rate, and complications were analyzed. Complete ablation was achieved in 10 patients (83.3%), and the alpha-fetoprotein level was also decreased to normal in these patients. The mean follow-up time was 13.3 ± 1.8 months (range, 2-25 months). At the end of follow-up, two patients died from tumor progression, the other 10 patients were alive. One patient was found to have lung metastasis after HIFU and had an operation to remove the lesion. The median survival time was 14 months, and the 1- and 2-year survival rates were 91.7% and 83.3%, respectively. Complications included fever, transient impairment of hepatic function, and mild malformation of ribs. Conclusion: HIFU combined with TACE is a safe and promising method with a low rate of severe complications. As a noninvasive approach, it may provide a novel local therapy for patients with unresectable hepatoblastoma. (Hepatology 2014;58:170–177)

Abbreviations
AFP

α-fetoprotein

CT

computed tomography

HIFU

high-intensity focused ultrasound

MRI

magnetic resonance imaging

TACE

transarterial chemoembolization

Hepatoblastoma is the most common malignant liver neoplasm in children. Although surgical resection is the mainstay of curative therapy for children with hepatoblastoma, only one-third to one-half of newly diagnosed patients with hepatoblastoma can be expected to have resectable disease at presentation. The main determinants of clinical outcome in patients with hepatoblastoma are the presence or absence of metastatic disease and tumor respectability.[1] Cooperative group studies from around the world performed in the late 1980s and early 1990s demonstrated the effectiveness of chemotherapy in increasing rates of surgical resection and survival in initially unresectable patients.[2] Recent clinical trials have revealed a significantly improve survival, and to date the 3-year event-free survival (EFS) and overall survival (OS) are ∼84% and 94%% in the PRETEXT III patients, 73% and 75% in PRETEXT IV patients, respectively.[3, 4] However, due to the shortage of liver donors, the survival rate is still unsatisfactory in hepatoblastoma patients in China, especially in those with initial unresectable hepatoblastoma.

Transarterial chemoembolization (TACE) is a highly practical and effective alternative, in which the chemotherapeutic drugs are selectively injected into the tumor-feeding arteries. The purpose of performing TACE is to achieve the cytoreduction of vital tumor tissue. After TACE, viable tumor cells still remain and may cause local recurrence and distant metastasis. For these reason, TACE has been used in combination with ablative therapies to exterminate residual tumor cells after TACE. High-intensity focused ultrasound (HIFU) ablation is a conformal extracorporeal treatment method that can noninvasively cause complete coagulation necrosis of large lesions without surgical exposure or insertion of instruments.[5] In recent years, HIFU has been applied experimentally to ablate normal liver tissue and implanted liver tumors in vivo, as well as human hepatocellular carcinoma (HCC), breast cancer, osteosarcoma, and prostate cancer.[6, 7] However, these are no attempts in pediatric populations. In this study we hypothesized that focused ultrasound ablation combined with TACE would be an effective treatment of advanced hepatoblastoma. Thus, the purpose of our study was to evaluate the use of HIFU ablation combined with TACE in the treatment of initially unresectable hepatoblastoma in children.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
Patients

From January 2009 to October 2011, 12 consecutive patients with initially unresectable hepatoblastoma were enrolled in our study, approved by the Ethics Committee at Chongqing Medical University. They were classified by PRETEXT system as stage III and IV hepatoblastoma, and no metastasis was detected at presentation in any of the enrolled patients. A detailed written description of the procedure was provided to all patients' parents before enrollment and informed consent was obtained before treatment.

Each patient was initially evaluated by three senior surgical oncologists working together, each of whom had more than 8 years of clinical experience, to determine suitability for surgery according to the PRETEXT staging. Patients were excluded from undergoing surgical resection on the basis of the following criteria: tumor proximity to major vascular structures, which precluded the resection of a tumor-free margin; presence of multiple lesions; or presence of insufficient hepatic functional reserve to tolerate conventional resection. The selection criteria for enrollment in our study were: hepatoblastoma diagnosis confirmed at ultrasound (US)-guided fine-needle biopsy or on the basis of both the characteristic findings of hepatoblastoma lesions shown at imaging (including color Doppler US, computed tomography [CT], and magnetic resonance imaging [MRI]) and a high level (more than 36,300 ng/mL) of serum α-fetoprotein (AFP), and no history of hepatic encephalopathy. All patients had stable hematogenic parameters and no active infection.

Table 1 summarizes the characteristics in all 12 patients. Patient age ranged from 3 months to 4 years. There were six males and six females. All the patients were stage III (n = 5) and IV (n = 7), AFP levels were all above 36,300 ng/mL (as the highest threshold of our lab). The tumors were 65-160 mm in diameter (mean: 116 ± 8.3 mm).

Table 1. Characteristics of All 12 Patients
Patient No. /Age/SexPRETEXT StageAFP Level at Diagnosis (Normal <6 ng/mL)Tumor Diameter at Diagnosis (mm)AFP Level After TACE (ng/mL)Tumor Diameter After TACE ( mm)AFP Level After HIFU (ng/mL)Tumor Diameter After HIFU (mm)Survival Time (m)Follow- up Time (m)Outcome at Last Follow-up
  1. AFP: α-fetoprotein; TACE: transarterial chemoembolization; HIFU: high-intensity focused ultrasound.

1/3m/MIII>36300087 × 96 × 105426145 × 50 × 612.332 × 34 × 403020alive, no evidence of disease
2/8m/FIII>36300079 × 88 × 8091541 × 42 × 421.431 × 31 × 302416alive, no evidence of disease
3/1y/FIII>36300067 × 84 × 951102039 × 52 × 635.225 × 32 × 352012alive, no evidence of disease
4/1y5m/MIV>36300089 × 78 × 751851 × 42 × 463.935 × 29 × 30188alive, no evidence of disease
5/1y2m/FIV>36300065 × 56 × 4931436 × 30 × 293.610 × 10 × 123525alive, no evidence of disease
6/11m/FIV>363000102 × 123 × 135153160 × 75 × 842.836 × 41 × 422616alive, no evidence of disease
7/1y7m/MIII>36300090 × 100 × 11012560 × 56 × 624.135 × 29 × 36102alive, no evidence of disease
8/2y1m/FIV>363000112 × 120 × 1251055064 × 65 × 72872030 × 35 × 402010died due to disease progression
9/1y4m/FIV>363000120 × 128 × 1391670 × 65 × 672.942 × 32 × 36167alive, no evidence of disease
10/2y2m/MIV>36300099 × 118 × 142454 × 60 × 714.229 × 32 × 432315alive, no evidence of disease
11/3y7m/MIII>363000119 × 120 × 14710252 × 56 × 554.831 × 35 × 272719alive, no evidence of disease
12/4y2m/MIV>363000100 × 120 × 160>36300069 × 85 × 102>36300060 × 78 × 90165died due to disease progression
Chemotherapeutic Procedures

Before TACE and HIFU treatments, each patient received two cycles of modified C5V regimen (cisplatin: 100 mg/m2/dose D1; 5-fluorouracil: 600 mg/m2/dose D3; vincristine: 1.5 mg/m2/dose D3), followed by a reassessment to determine tumor response. If a partial response was achieved, TACE combined with HIFU was then performed. If unsatisfactory, two more C5VD regimens were subsequently administered for these patients (cisplatin: 100 mg/m2/dose D1; 5-fluorouracil: 600 mg/m2/dose D3; vincristine: 1.5 mg/m2/dose D3; doxorubicin: 10-15 mg/m2/dose D4). No patient needed to be omitted from the study due to the toxicity of doxorubicin.

After the patients finished the initial chemotherapy cycles, they underwent CT/MRI examination again. A reassessment was subsequently performed by the Pediatric Oncology team to evaluate the tumor response. It was obvious that the tumor blood supply was significantly reduced after chemotherapy, and the margin between the tumor and normal liver was much clearer. The tumor size also decreased after chemotherapy in all patients. Based on the follow-up radiological findings, 6 of 12 patients would be able to undergo a partial hepatectomy after chemotherapy due to the decreased tumor size. However, their parents all refused the surgical procedure, although our team discussed with them several times how important the hepatectomy is in terms of a cure method for hepatoblastoma. They hoped to continue the trial protocol due to the noninvasive nature of HIFU treatment.

After TACE combined with HIFU treatments, all patients received at least four cycles of adjuvant chemotherapy with C5V regimen. The AFP levels decreased steadily except in one patient with a tumor embolus in the portal vein (patient no. 12).

TACE Procedures

All patients received TACE before HIFU ablation. TACE was performed by two interventional radiologists with the use of the Seldinger technique of arterial embolization described previously.[8] Under general anesthesia, the femoral artery is cannulated using the Seldinger technique and a 4- or 5-F sheath with a hemostatic valve is placed in the groin. Then hepatic arteriography was performed to demonstrate the hepatic arterial branching and size and location of tumor. According to the size, location, and arterial blood supply of the tumors, either the right or left hepatic artery was catheterized selectively guided by digital subtraction angiography. A 3- to 5-F tracker catheter was catheterized to the feeding arteries of tumors for superselective embolization. The feeding arteries of all tumors were embolized with the use of the suspension mixed with either 100 mg/m2 of Carboplatin (Qilu Pharmaceutical Factory, Jinan, China) or 10-15 mg/m2 of adriamycin (Pfizer, Nerviano, Italy) and 3-8 mL of iodized oil (Lipiodol; Huaihai Pharmaceutical Factory, Shanghai, China). After initial chemotherapy, the tumor size was significantly decreased in all patients. However, there were six patients with lesions in both lobes of the liver. They received highly selective TACE for both lobes, and one or more small feeding arteries of the tumors were superselectively embolized, instead of the left and right branch of the hepatic artery. All of them tolerated highly selective TACE well, as the residual volume of the normal liver was maintained at least more than 40% the total volume of the liver in each case. In this study 11 patients underwent one-session TACE, and one patient received a second TACE due to unsatisfactory shrinkage of the tumor.

Preparation Before HIFU Treatment

Plain CT was performed to evaluate the lipiodol deposition of the lesions in all patients 7-10 days after each TACE. Conventional serum chemical tests including liver biochemical tests, complete blood cell counts, prothrombin time, and AFP were detected before ablation. In addition, chest radiography, abdominal ultrasonography, and electrocardiogram (ECG) were assessed before HIFU ablation. Enhanced CT or MRI was applied to evaluate the information of each tumor including its size, location, number, and enhancement before treatment and periodically after HIFU ablation.

HIFU Treatment Procedure

The device used for the HIFU procedure was a Model-JC200 HIFU system (Chongqing Haifu (HIFU) Tech, Chongqing, China). It consisted of US therapy transducers with a US generator, a real-time diagnostic US device, a six-direction movement system, computer units for automated control, a treatment bed, and a degassed water circulation unit. A 12-cm diameter PZT-4 piezo-ceramic transducer was employed to produce therapeutic US energy. The frequency of the transducers was 0.8 MHz, with various focal lengths ranging from 135 to 155 mm. A US imaging device (Esaote DU3, Genova, Italy) was used as a real-time imaging guidance in the HIFU system, with a 2.5-3.5 MHz probe. This diagnostic probe was situated in the center of the HIFU transducer, and the integrated transducer was then placed in the bag filled with degassed water. HIFU procedure was performed 2-3 weeks after TACE. All patients received general anesthesia for HIFU treatment, which prevented patient discomfort and mobilization. After suitable anesthesia was achieved, the patient was positioned either prone or on his or her right side, so that the skin overlaying the targeted lesion would be easily put in contact with the degassed water. With movement of the integrated transducer, the targeted liver tumor was clearly identified on US imaging, and the targeted volume was divided into parallel slices of 5-mm separation. The operator outlined the margin of the treated region in each of the slices, including the tumor and at least 1 cm of normal tissue surrounding the tumor. The range of the target of the each slice was automatically recorded by the computer in three orthogonal directions. After a detailed planning session was finished, a linear scanning track of HIFU exposure was selected as an ablative scheme. Using provisional therapeutic parameters based on the depth and vascular supply of the target region, the tumor on each slice was completely ablated from the deep to shallow regions, and this process was repeated slice by slice to achieve entire tumor treatment. Gray-scale changes obtained on the diagnostic images within the focus after each HIFU exposure were used during the ablative procedure to identify and monitor the extent of treatment.[9] In this study acoustic power used for ablation ranged from 181 to 256 W, and HIFU exposure time varied from 30 to 202 minutes, which was dependent on the size of the targeted tumors. All patients received one HIFU session. Two patients needed artificial pleural effusion to treat tumor near the diaphragm by revealing lesions obscured by lung tissues. It was performed under the guidance of diagnostic US imaging after general anesthesia was introduced. Then 150-300 mL saline was perfused into the pleural cavity using a thoracentesis needle. The puncture point was located at axillary line 6-7 intercostal space in the right chest wall. No patient received a second HIFU treatment in the clinical trial.

Follow-up

Results of follow-up Doppler US revealed that the tumor margin was clearly identified 2 weeks after HIFU ablation. An increase in grayscale was seen in 11 patients. No tumor blood supply was detected in any patient except no. 12. All 12 patients were followed up after HIFU ablation, color Doppler US and contrast-enhanced CT or MRI was used as the main follow-up radiological assessment in all patients. The first CT/MRI examination was performed 2 weeks after HIFU treatment while inflammatory edema disappeared completely at the marginal area of the ablated tumor. Compared to CT/MRI images before HIFU, an obvious absence of contrast enhancement was found in the treated tumor after HIFU, which was an indication of coagulation necrosis. In addition, a thin contrast-enhancement ring observed between the treated and untreated regions was very useful to assess whether tumor cells remained after HIFU ablation. If the residual viable tumor was demonstrated on the follow-up CT/MRI, a subsequent HIFU ablation was carried out for destruction of the remaining tumor 1-4 weeks after CT/MRI examination. Each patient was followed up every 3 months after the combined therapy. Serum biochemistry and clinical examination were also performed during follow-up.

Statistical Analysis

All data are reported as the mean ± standard deviation. Statistical analysis was performed by a statistical software package (SPSS v. 13.0). The period of follow-up was defined as the time from the completion of adjuvant chemotherapy to death or last follow-up. The Kaplan-Meier method was used to assess overall survival. P values were judged significant if they were less than 0.05.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
Tumor Response

Contrast-enhanced CT/MRI and Doppler US was performed before and after HIFU ablation. The short-term effectiveness of HIFU ablation was assessed by CT/MRI and US at 2 weeks after HIFU. The disappearance of the enhancement and blood flow signal within the treated tumor was found on radiological images after HIFU as compared with before HIFU (Figs. 1, 2). This was seen as an indication of complete ablation. In our study, contrast-enhanced CT/MRI at 2 weeks after HIFU ablation showed that tumors were completely ablated in 10 patients (83.3%). The AFP level also decreased to normal in these patients, which indicated a good response to both TACE+HIFU treatment and chemotherapy. The ablation target for patient no. 12 was the embolus in the portal vein and partial tumor. Before HIFU ablation, no blood flow of the portal vein was detectable on US; in contrast, blood flow was visible after HIFU ablation and the blood flow of the tumor also decreased after HIFU. However, the AFP level did not decrease and the patient died 4 months after HIFU.

image

Figure 1. (A) Contrast-enhanced CT at presentation revealed a large liver tumor arising from the right hepatic lobe. (B) Contrast-enhanced CT after four cycles of chemotherapy revealed reduction in tumor size. (C) Contrast-enhanced CT after TACE revealed a concentration of lipiodol in the tumor. (D) Contrast-enhanced CT 1 month after HIFU revealed the tumor was completely ablated, with no blood supply. (E) Contrast-enhanced CT 6 months after HIFU revealed the tumor with no blood supply and the lesion was absorbed gradually. (F) Contrast-enhanced CT 12 months after HIFU revealed the tumor was completely ablated, with no blood supply and the lesion was absorbed gradually.

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image

Figure 2. (A) Contrast-enhanced CT at presentation revealed a large liver tumor arising from the right hepatic lobe. (B) Contrast-enhanced CT after four cycles of chemotherapy revealed reduction in tumor size. (C) Contrast-enhanced CT after TACE revealed a concentration of lipiodol in the tumor. (D) Contrast-enhanced CT 1 month after HIFU revealed the tumor was completely ablated, with no blood supply and the lesion was absorbed gradually. (E) MRI 6 months after HIFU revealed the tumor was completely ablated, with no blood supply. (F) Contrast-enhanced CT 1 year after HIFU revealed the tumor was completely ablated, with no blood supply and the lesion was absorbed gradually.

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Survival

All patients achieved follow-up. The mean period of follow-up was 13.3 ± 1.8 months (range, 2-25 months). At the time of last follow-up, two patients (patients 8 and 12) had died from tumor progression. One patient (patient 11) presented with elevated AFP which once decreased to normal, and CT scan revealed lung metastasis. After surgical resection of the metastasis lesion, the AFP decreased to normal 1 month later. Overall survival was assessed using the Kaplan-Meier method. The median survival time was 21.5 months, and the survival rates at 1 and 2 years were 91.7% and 83.3%, respectively. The survival curve of patients in this study is shown in Fig. 3.

image

Figure 3. The survival rate of stage III and stage IV patients.

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Complications

Among all patients treated with HIFU ablation, an extremely low rate of major complications was observed compared to conventional surgery for hepatoblastoma. All patients tolerated the HIFU procedure well. There were no signs of liver bleeding and infection or damage to adjacent organs such as the gallbladder, bile duct, bowels, and stomach after HIFU treatment. Three patients had a fever with temperature >39°C for 5 days after HIFU ablation. There were no serious skin burns induced by HIFU ablation. All patients had a transient impairment of hepatic function, mainly presented with elevated aminotransferase, which returned to normal 2 weeks after HIFU ablation. No major blood vessel injury was observed. There were no hemorrhagic accidents during or after treatment and no damage to bile ducts was seen. Only two patients were found to have mild malformation of ribs.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

Hepatoblastoma is a highly malignant embryonal liver tumor that almost exclusively occurs in infants and toddlers. Improvements in radiologic imaging, advances in chemotherapy, improved surgical techniques, and advances in liver transplantation have shown overall improvement in the outcome of children with hepatoblastoma. The most important factor determining the outcome in children with hepatoblastoma is a combination of complete surgical resection and chemotherapy. It has consistently resulted in improved resectability and survival.[10, 11] However, about half of all children with hepatoblastoma have unresectable tumors at presentation,[12] and novel treatment approaches should be considered for the unresectable patients, in addition to liver transplantation.

Unresectable bulky tumors have a definitely dismal prognosis unless chemotherapy and/or TACE reduces the tumor volume and makes total resection possible. Various chemotherapy protocols have been conducted for this purpose. Several protocols, including cisplatin and doxorubicin, have been reported to have a response rate over 90%.[3, 4] However, systemic chemotherapy has its limitations because of the adverse effects caused by the chemotherapeutic agents. Selective administration of chemotherapeutic agents through the hepatic artery was used in this clinical study. It can be combined with arterial embolization to occlude feeding arteries and induce ischemic tumor necrosis, which enhances its effect.[13] In our study, the diameter of tumors all decreased and the AFP levels all dropped obviously after TACE. In addition, a potential role of neoadjuvant chemotherapy and AFP half-life dynamics as potential confounding factors might also account for the continued AFP drop.

HIFU ablation is an extracorporeal treatment method that can noninvasively cause complete coagulation necrosis of large lesions without surgical exposure, and it has been increasingly used in adult solid tumors.[14, 15] An extracorporeal MR-guided HIFU device has been approved by the Food and Drug Administration (FDA) in the United States for clinical treatment of uterine fibroids, and a US-guided HIFU device has also been used in Europe for treating both benign and malignant tumors after Ethics Committee approval.[16-18] However, there is little literature concerning the pediatric population. We reported the first attempt of a successful ablation of recurrence hepatocellular carcinoma in a child, and we suggested that HIFU might be considered as another treatment option for children with liver masses.[19] Here we presumed that HIFU ablation was as effective as surgery in treating hepatoblastoma. Therefore, all patients received HIFU ablation after TACE treatment. The result was promising. All stage III and five stage IV patients achieved complete ablation, and the tumor shrank to 40%-50% of its previous volume. More important, the blood flow of treated tumor was absent on color Doppler US. Compared to CT/MRI images before HIFU, an absence of contrast enhancement was also found, which indicated coagulation necrosis. The tumor marker AFP decreased to normal in 10 patients. Only two patients died from tumor progression; however, there was an impact of HIFU, as the volume of tumor was smaller and the AFP level was also decreased in one patient. The overall survival rates at 1 and 2 years were 91.7% and 83.3%, respectively, suggesting that the combination of TACE+HIFU with chemotherapy could be used as a salvage treatment for patients with unresected hepatoblastoma. However, large-scale clinical trials are necessary in the future if the combined therapy becomes a conventional treatment for children with hepatoblastoma, including the establishment of the indications of HIFU combined with TACE for hepatoblastoma.

From our experience, we emphasize the importance of TACE before HIFU ablation. The two reasons TACE can enhance the therapeutic effect of HIFU are: (1) the effect of embolism by TACE can reduce blood flow in the tumor capable of causing heat loss during HIFU therapy, and (2) iodinated oil. The agent used for TACE embolism is deposited in the tumor, thus creating greater acoustic impedance than liver tissue.[20] Deposition of iodinated oil not only has a positioning function, but also has a synergistic effect of temperature rise similar to HIFU. Therefore, it provides a strong thermogenic action promoting the therapeutic effects of HIFU.

Major differences of MR- and US-guided HIFU therapy from other interventional therapies are its complete noninvasiveness of treatment with very low complication rates. After HIFU ablation, most patients have a favorable general condition and stable vital signs. An increased transaminase level was seen in most patients with larger tumors,21 as in our study, and an elevated transaminase level was observed in all patients; however, the results returned to normal within 2 weeks of therapy. Only three patients had a fever with temperature >39°C for 5 days after HIFU ablation. Skin-burn was a relatively common complication after HIFU: about 4.1% patients had serious skin burn in Jin et al.'s study,[9] especially in those patients whose tumor was located superficially. However, there was no skin burn observed in our study. We also found a new complication that was not reported before in the adult population. Two patients were found to have mild malformation of ribs at follow-up. The potential mechanism may be interpreted as direct injury by high-energy US waves or indirect injury by elevated temperature of surrounding tissues. No rib fracture was seen in our series. We considered HIFU ablation in children with hepatoblastoma a safe procedure without serious complications. However, the number of our cases was limited and larger series are critical to draw a convincing conclusion.

In conclusion, our experience of the 12 cases, although small in number, suggests the advantages HIFU combined with TACE. HIFU has great developmental prospects for treating hepatoblastoma as a noninvasive treatment method with advantages of accurate location, noninvasive “resection,” radioactive decontamination, and low complication rates. However, HIFU for pediatric tumor is still in its beginning and requires further study and large-scale randomized clinical trails to confirm our observations and to further determine the role of HIFU.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
  • 1
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    Kim HS, Baik JH, Pham LD, Jacobs MA. MR-guided high-intensity focused ultrasound treatment for symptomatic uterine leiomyomata: long-term outcomes. Acad Radiol 2011;18:970-976.
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    Wang S, Kong X-r, Yang C, Zhang J, Li C-c, Ouyang J, et al. Extracorporeal high intensity focused ultrasound treatment for a child with recurrence of hepatocellular carcinoma. Eur J Radiol Extra 2010;75:e101-e103.
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    Shen HP, Gong JP, Zuo GQ. Role of high-intensity focused ultrasound in treatment of hepatocellula rcarcinoma. Am Surg 2011;77:1496-1501.