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Wu S, Li Z, Yao C, Dong S, Gao J, Ke S, Zhu R, Huang S, Wang S, Xu L, Ye C, Kong J, Sun W. Progression of hepatocellular carcinoma after radiofrequency ablation: Current status of research. Front Oncol 2022; 12:1032746. [PMID: 36483051 PMCID: PMC9723167 DOI: 10.3389/fonc.2022.1032746] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/04/2022] [Indexed: 05/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) remains an important disease for health care systems in view of its high morbidity, mortality, and increasing incidence worldwide. Radiofrequency ablation (RFA) is preferred to surgery as a local treatment for HCC because it is safer, less traumatic, less painful, better tolerated, causes fewer adverse reactions, and allows more rapid postoperative recovery. The biggest shortcoming of RFA when used to treat HCC is the high incidence of residual tumor, which is often attributed to the vascular thermal deposition effect, the wide infiltration zone of peripheral venules, and the distance between satellite foci and the main focus of the cancer. Recurrence and progression of the residual tumor is the most important determinant of the prognosis. Therefore, it is important to be aware of the risk of recurrence and to improve the efficacy of RFA. This review summarizes the relevant literature and the possible mechanisms involved in progression of HCC after RFA. Current studies have demonstrated that multimodal treatments which RFA combined with other anti-cancer approaches can prevent progression of HCC after RFA.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Jian Kong
- Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Wenbing Sun
- Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China
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Bockorny B, Bullock AJ, Abrams TA, Faintuch S, Alsop DC, Goldberg SN, Ahmed M, Miksad RA. Priming of Sorafenib Prior to Radiofrequency Ablation Does Not Increase Treatment Effect in Hepatocellular Carcinoma. Dig Dis Sci 2022; 67:3455-3463. [PMID: 34297268 DOI: 10.1007/s10620-021-07156-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 07/05/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Preclinical studies have shown that modulation of the tumor microvasculature with anti-angiogenic agents decreases tumor perfusion and may increase the efficacy of radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC). Retrospective studies suggest that sorafenib given prior to RFA promotes an increase in the ablation zone, but prospective randomized data are lacking. AIMS We conducted a randomized, double-blind, placebo-controlled phase II trial to evaluate the efficacy of a short-course of sorafenib prior to RFA for HCC tumors sized 3.5-7 cm (NCT00813293). METHODS Treatment consisted of sorafenib 400 mg twice daily for 10 days or matching placebo, followed by RFA on day 10. The primary objectives were to assess if priming with sorafenib increased the volume and diameter of the RFA coagulation zone and to evaluate its impact on RFA thermal parameters. Secondary objectives included feasibility, safety and to explore the relationship between tumor blood flow on MRI and RFA effectiveness. RESULTS Twenty patients were randomized 1:1. Priming with sorafenib did not increase the size of ablation zone achieved with RFA and did not promote significant changes in thermal parameters, although it significantly decreased blood perfusion to the tumor by 27.9% (p = 0.01) as analyzed by DCE-MRI. No subject discontinued treatment owing to adverse events and no grade 4 toxicity was observed. CONCLUSION Priming of sorafenib did not enhance the effect of RFA in intermediate sized HCC. Future studies should investigate whether longer duration of treatment or a different antiangiogenic strategy in the post-procedure setting would be more effective in impairing tumor perfusion and increasing RFA efficacy.
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Affiliation(s)
- Bruno Bockorny
- Beth Israel Deaconess Medical Center, Boston, MA, USA. .,Harvard Medical School, Boston, MA, USA.
| | - Andrea J Bullock
- Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Thomas A Abrams
- Harvard Medical School, Boston, MA, USA.,Dana Farber Cancer Institute, Boston, MA, USA
| | - Salomao Faintuch
- Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - David C Alsop
- Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - S Nahum Goldberg
- Beth Israel Deaconess Medical Center, Boston, MA, USA.,Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Muneeb Ahmed
- Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Rebecca A Miksad
- Boston Medical Center, Boston University, Boston, MA, USA.,Flatiron Health, New York, NY, USA
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Degrauwe N, Hocquelet A, Digklia A, Schaefer N, Denys A, Duran R. Theranostics in Interventional Oncology: Versatile Carriers for Diagnosis and Targeted Image-Guided Minimally Invasive Procedures. Front Pharmacol 2019; 10:450. [PMID: 31143114 PMCID: PMC6521126 DOI: 10.3389/fphar.2019.00450] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 04/08/2019] [Indexed: 12/12/2022] Open
Abstract
We are continuously progressing in our understanding of cancer and other diseases and learned how they can be heterogeneous among patients. Therefore, there is an increasing need for accurate characterization of diseases at the molecular level. In parallel, medical imaging and image-guided therapies are rapidly developing fields with new interventions and procedures entering constantly in clinical practice. Theranostics, a relatively new branch of medicine, refers to procedures combining diagnosis and treatment, often based on patient and disease-specific features or molecular markers. Interventional oncology which is at the convergence point of diagnosis and treatment employs several methods related to theranostics to provide minimally invasive procedures tailored to the patient characteristics. The aim is to develop more personalized procedures able to identify cancer cells, selectively reach and treat them, and to assess drug delivery and uptake in real-time in order to perform adjustments in the treatment being delivered based on obtained procedure feedback and ultimately predict response. Here, we review several interventional oncology procedures referring to the field of theranostics, and describe innovative methods that are under development as well as future directions in the field.
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Affiliation(s)
- Nils Degrauwe
- Department of Diagnostic and Interventional Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Arnaud Hocquelet
- Department of Diagnostic and Interventional Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Antonia Digklia
- Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Niklaus Schaefer
- Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Alban Denys
- Department of Diagnostic and Interventional Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Rafael Duran
- Department of Diagnostic and Interventional Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Thompson SM, Jondal DE, Butters KA, Knudsen BE, Anderson JL, Roberts LR, Callstrom MR, Woodrum DA. Heat Stress and Thermal Ablation Induce Local Expression of Nerve Growth Factor Inducible (VGF) in Hepatocytes and Hepatocellular Carcinoma: Preclinical and Clinical Studies. Gene Expr 2018; 19:37-47. [PMID: 29973305 PMCID: PMC6290322 DOI: 10.3727/105221618x15305531034617] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The purposes of this study were to test the hypothesis that heat stress and hepatic thermal ablation induce nerve growth factor inducible (VGF) and to determine intrahepatic versus systemic VGF expression induced by thermal ablation in vivo and in patients. Hepatocytes and HCC cells were subjected to moderate (45°C) or physiologic (37°C) heat stress for 10 min and assessed for VGF expression at 0-72 h post-heat stress (n ≥ 3 experiments). Orthotopic N1S1 HCC-bearing rats were randomized to sham or laser thermal ablation (3 W × 90 s), and liver/serum was harvested at 0-7 days postablation for analysis of VGF expression (n ≥ 6 per group). Serum was collected from patients undergoing thermal ablation for HCC (n = 16) at baseline, 3-6, and 18-24 h postablation and analyzed for VGF expression. Data were analyzed using ordinary or repeated-measures one-way analysis of variance and post hoc pairwise comparison with Dunnett's test. Moderate heat stress induced time-dependent VGF mRNA (3- to 15-fold; p < 0.04) and protein expression and secretion (3.1- to 3.3-fold; p < 0.05). Thermal ablation induced VGF expression at the hepatic ablation margin at 1 and 3 days postablation but not remote from the ablation zone or distant intrahepatic lobe. There was no detectable serum VGF following hepatic thermal ablation in rats and no increase in serum VGF following HCC thermal ablation in patients at 3-6 and 18-24 h postablation compared to baseline (0.71- and 0.63-fold; p = 0.27 and p = 0.16, respectively). Moderate heat stress induces expression and secretion of VGF in HCC cells and hepatocytes in vitro, and thermal ablation induces local intrahepatic but not distant intrahepatic or systemic VGF expression in vivo.
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Affiliation(s)
- Scott M. Thompson
- *Department of Radiology, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Danielle E. Jondal
- *Department of Radiology, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Kim A. Butters
- *Department of Radiology, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Bruce E. Knudsen
- *Department of Radiology, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Jill L. Anderson
- *Department of Radiology, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Lewis R. Roberts
- †Division of Gastroenterology and Hepatology, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Matthew R. Callstrom
- *Department of Radiology, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, USA
| | - David A. Woodrum
- *Department of Radiology, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, USA
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Fukuda H, Numata K, Hara K, Nozaki A, Kondo M, Chuma M, Nakano M, Nozawa A, Maeda S, Tanaka K. Comparison of vascularity observed using contrast-enhanced 3D ultrasonography and pathological changes in patients with hepatocellular carcinoma after sorafenib treatment. J Cancer 2018; 9:2408-2414. [PMID: 30026837 PMCID: PMC6036707 DOI: 10.7150/jca.24236] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 04/15/2018] [Indexed: 12/12/2022] Open
Abstract
Aim: The aim of this study was to compare vascularity observed using contrast-enhanced 3D ultrasonography and pathological changes in human hepatocellular carcinoma (HCC) and surrounding non-tumorous areas after sorafenib treatment. Materials and methods: Twelve patients with HCC were enrolled in this clinical study. The maximum tumor diameter as measured using sonography ranged from 15 to 33 mm (mean, 24.0 mm; SD, 5.7 mm). Assessments using contrast-enhanced (0.2 mL of Sonazoid suspension; Daiichi Sankyo, Tokyo, Japan) 3D ultrasonography (LOGIQ 7; GE Healthcare, Milwaukee) were performed in all the patients before and 1 week after sorafenib treatment. The microvessel density (MVD) of the HCC and surrounding non-tumorous area was evaluated based on the immunohistochemical staining of microvessels using an antigen for CD34. Results: Blood flow in the tumor was decreased in all 12 cases after sorafenib treatment. The MVD of the tumorous area at 1 week after sorafenib administration (38.8 ± 5.2) was significantly lower than that observed before sorafenib administration (72.4 ± 13.0) (P < 0.01). Blood flow in the non-tumorous area had decreased in 6 cases at 1 week after sorafenib treatment and had not changed in the 6 other cases. In the reduced blood flow group, the MVD of the non-tumorous area at 1 week after sorafenib administration had decreased significantly, compared with the MVD of the non-tumorous area before sorafenib administration. However, in the group with no change in blood flow, the MVD of the non-tumorous area at 1 week after sorafenib treatment had not changed, compared with the MVD of the non-tumorous area before sorafenib treatment. Conclusion: Contrast-enhanced 3D ultrasonography studies showed a correlation between vascularity and pathological changes in human HCC and the surrounding non-tumorous area after sorafenib treatment.
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Affiliation(s)
- Hiroyuki Fukuda
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan
| | - Kazushi Numata
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan
| | - Koji Hara
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan
| | - Masaaki Kondo
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan
| | - Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan
| | - Masayuki Nakano
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan
| | - Akinori Nozawa
- Department of Pathology, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan
| | - Katsuaki Tanaka
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan
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Jondal DE, Thompson SM, Butters KA, Knudsen BE, Anderson JL, Carter RE, Roberts LR, Callstrom MR, Woodrum DA. Heat Stress and Hepatic Laser Thermal Ablation Induce Hepatocellular Carcinoma Growth: Role of PI3K/mTOR/AKT Signaling. Radiology 2018; 288:730-738. [PMID: 29737948 DOI: 10.1148/radiol.2018172944] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Purpose To determine if heat stress and hepatic laser thermal ablation induce hepatocellular carcinoma (HCC) growth and to identify growth factors induced by heat stress. Materials and Methods Non-heat-stressed HCC cells were cocultured with HCC cells or hepatocytes that were heat stressed at 37°C (physiologic), 45°C (moderate), or 50°C (severe) for 10 minutes and proliferation monitored with bioluminescence imaging for up to 6 days after heat stress (three experiments). Rats bearing orthotopic N1S1 HCC were randomly assigned to undergo immediate sham or laser thermal (3 W for 60 or 90 seconds; hereafter, 3W×60s and 3W×90s, respectively) ablation of the median (local) or left (distant) hepatic lobe, and tumor growth was monitored with magnetic resonance imaging for up to 18 days after ablation (six or more rats per group). Experiments were repeated with rats randomly assigned to receive either the adjuvant phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor (NVP-BEZ235) or the vehicle control. Heat-stressed HCC cells and hepatocytes were analyzed by using microarray or quantitative real-time polymerase chain reaction analysis for growth factor expression (three or more experiments). Groups were compared by using one- or two-way analysis of variance, and post hoc pairwise comparison was performed with the Dunnett test. Results There were more non-heat-stressed HCC cells when cells were cocultured with cells subjected to moderate but not physiologic or severe heat stress (P < .001 for both). Local intrahepatic N1S1 tumors were larger at day 18 in the 3W×60s (mean, 3102 mm3 ± 463 [standard error]; P = .004) and 3W×90s (mean, 3538 mm3 ± 667; P < .001) groups than in the sham group (mean, 1363 mm3 ± 361) but not in distant intrahepatic tumors (P = .31). Adjuvant BEZ235 resulted in smaller N1S1 tumors in the BEZ235 and laser thermal ablation group than in the vehicle control and laser thermal ablation group (mean, 1731 mm3 ± 1457 vs 3844 mm3 ± 2400, P < .001). Moderate heat stress induced expression of growth factors in HCC cells and hepatocytes, including heparin-binding growth factor, fibroblast growth factor 21, and nerve growth factor (range, 2.9-66.9-fold; P < .05). Conclusion Moderate heat stress and laser thermal ablation induce hepatocellular carcinoma growth, which is prevented with adjuvant PI3K/mTOR/protein kinase B inhibition.
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Affiliation(s)
- Danielle E Jondal
- From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.)
| | - Scott M Thompson
- From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.)
| | - Kim A Butters
- From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.)
| | - Bruce E Knudsen
- From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.)
| | - Jill L Anderson
- From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.)
| | - Rickey E Carter
- From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.)
| | - Lewis R Roberts
- From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.)
| | - Matthew R Callstrom
- From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.)
| | - David A Woodrum
- From the Department of Radiology (D.E.J., S.M.T., K.A.B., B.E.K., J.L.A., M.R.C., D.A.W.) and Division of Gastroenterology and Hepatology (L.R.R.), Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Health Sciences Research, Mayo Clinic School of Medicine, Jacksonville, Fla (R.E.C.)
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Advantage of sorafenib combined with radiofrequency ablation for treatment of hepatocellular carcinoma. TUMORI JOURNAL 2016; 103:286-291. [PMID: 28058713 DOI: 10.5301/tj.5000585] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Among the surgical and nonsurgical treatments available, radiofrequency ablation (RFA) and sorafenib have been shown to have efficacy. There is little evidence whether combination of these therapies would have additional benefits. METHODS In a mouse model of HCC, effects of sorafenib were determined by tumor size, RFA-induced necrosis area (triphenyltetrazolium chloride staining), microvascular density (MVD; 4',6-diamidino-2-phenylindole and anti-CD31 antibody staining), and tumor perfusion (magnetic resonance imaging). RESULTS The RFA-induced necrosis area was 80.98 ± 9.14 and 69.49 ± 7.46 mm2 in mice administered 80 and 40 mg/kg sorafenib, respectively, but only 57.29 ± 3.39 mm2 in controls. Sorafenib also reduced tumor volume and enhanced RFA-induced tumor destruction in a dose-dependent manner, and reduced both MVD and tumor perfusion. CONCLUSIONS The results of our study suggest a potential role for combining RFA with sorafenib for treatment of HCC. Sorafenib could enhance RFA efficiency, possibly through its angiogenesis suppressive effects.
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Bulvik BE, Rozenblum N, Gourevich S, Ahmed M, Andriyanov AV, Galun E, Goldberg SN. Irreversible Electroporation versus Radiofrequency Ablation: A Comparison of Local and Systemic Effects in a Small-Animal Model. Radiology 2016; 280:413-24. [PMID: 27429143 DOI: 10.1148/radiol.2015151166] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Purpose To compare both periablational and systemic effects of two mechanistically different types of ablation: thermal radiofrequency (RF) ablation and electroporative ablation with irreversible electroporation (IRE) in appropriately selected animal models. Materials and Methods Animal experiments were performed according to a protocol approved by the Animal Care Committee of Hebrew University. Female C57BL/6 mice (n = 165) were randomized to undergo either RF or IRE ablation of noncancerous normal liver. The inflammatory response, cell proliferation, interleukin 6 (IL-6) levels, and intactness of vessels in the liver were assessed at 6, 12, and 24 hours and at 3, 7, and 14 days after ablation (n = 122 for mechanistic experiments). Systemic effects were then assessed by comparing tumor formation in an Mdr2-knockout (KO) mouse model (n = 15) and tumor growth in a remote BNL 1ME hepatoma xenograft tumor (n = 28). Results were averaged and evaluated by using two-tailed t tests. Results Although RF ablation was associated with a well-defined periablational inflammatory rim, for IRE, the infiltrate penetrated the ablation zone, largely along persistently patent vessels. Peak IL-6 levels (6 hours after ablation) were 10 and three times higher than at baseline for IRE and RF, respectively (P < .03). Mdr2-KO mice that were treated with IRE ablation had more tumors that were 3 mm or larger than mice treated with RF ablation or sham operation (mean, 3.6 ± 1.3 [standard deviation] vs 2.4 ± 1.1 and 2.2 ± 0.8, respectively; P < .05 for IRE vs both RF ablation and sham operation). For BNL 1ME tumors, both RF and IRE liver ablation reduced tumor growth, with a greater effect noted for IRE (1329 mm(3) ± 586 and 819 mm(3) ± 327 vs 2241 mm(3) ± 548 for sham operation; P < .05) that was accompanied by more infiltrating lymphocytes compared with sham operation (7.6 cells per frame ± 1.9 vs 11.2 ± 2.1 vs 0.3 ± 0.1; P < .05). Conclusion Persistent patency of vasculature within the coagulated zone from IRE increases the area and accumulation of infiltrative cells that is associated with a higher serum IL-6 level than RF ablation. These local changes of IRE induce more robust systemic effects, including both tumorigenic and immunogenic effects. (©) RSNA, 2016 Online supplemental material is available for this article.
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Affiliation(s)
- Baruch E Bulvik
- From the Goldyne Savad Institute of Gene Therapy (B.E.B., N.R., S.G., E.G., S.N.G.), Laboratory of Membrane and Liposome Research, Department of Biochemistry, Institute for Medical Research Israel-Canada (A.V.A.), and Department of Radiology (S.N.G.), Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; and Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (M.A., S.N.G.)
| | - Nir Rozenblum
- From the Goldyne Savad Institute of Gene Therapy (B.E.B., N.R., S.G., E.G., S.N.G.), Laboratory of Membrane and Liposome Research, Department of Biochemistry, Institute for Medical Research Israel-Canada (A.V.A.), and Department of Radiology (S.N.G.), Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; and Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (M.A., S.N.G.)
| | - Svetlana Gourevich
- From the Goldyne Savad Institute of Gene Therapy (B.E.B., N.R., S.G., E.G., S.N.G.), Laboratory of Membrane and Liposome Research, Department of Biochemistry, Institute for Medical Research Israel-Canada (A.V.A.), and Department of Radiology (S.N.G.), Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; and Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (M.A., S.N.G.)
| | - Muneeb Ahmed
- From the Goldyne Savad Institute of Gene Therapy (B.E.B., N.R., S.G., E.G., S.N.G.), Laboratory of Membrane and Liposome Research, Department of Biochemistry, Institute for Medical Research Israel-Canada (A.V.A.), and Department of Radiology (S.N.G.), Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; and Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (M.A., S.N.G.)
| | - Alexander V Andriyanov
- From the Goldyne Savad Institute of Gene Therapy (B.E.B., N.R., S.G., E.G., S.N.G.), Laboratory of Membrane and Liposome Research, Department of Biochemistry, Institute for Medical Research Israel-Canada (A.V.A.), and Department of Radiology (S.N.G.), Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; and Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (M.A., S.N.G.)
| | - Eithan Galun
- From the Goldyne Savad Institute of Gene Therapy (B.E.B., N.R., S.G., E.G., S.N.G.), Laboratory of Membrane and Liposome Research, Department of Biochemistry, Institute for Medical Research Israel-Canada (A.V.A.), and Department of Radiology (S.N.G.), Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; and Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (M.A., S.N.G.)
| | - S Nahum Goldberg
- From the Goldyne Savad Institute of Gene Therapy (B.E.B., N.R., S.G., E.G., S.N.G.), Laboratory of Membrane and Liposome Research, Department of Biochemistry, Institute for Medical Research Israel-Canada (A.V.A.), and Department of Radiology (S.N.G.), Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; and Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (M.A., S.N.G.)
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Chen L, Sun J, Yang X. Radiofrequency ablation-combined multimodel therapies for hepatocellular carcinoma: Current status. Cancer Lett 2015; 370:78-84. [PMID: 26472630 DOI: 10.1016/j.canlet.2015.09.020] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 09/13/2015] [Accepted: 09/23/2015] [Indexed: 12/21/2022]
Abstract
Radiofrequency ablation (RFA) is widely accepted as a first-line interventional oncology approach for hepatocellular carcinoma (HCC) and has the advantages of high treatment efficacy and low complication risk. Local control rates equivalent to hepatic resection can be reached by RFA alone when treating small HCCs (<2 cm) in favorable locations. However, local tumor progression and recurrence rates with RFA monotherapy increase sharply when treating larger lesions (>3 cm). To address this clinical problem, recent efforts have focused on multimodel management of HCC by combining RFA with different techniques, including percutaneous ethanol injection, transarterial chemo-embolization, targeted molecular therapy, nanoparticle-mediated therapy, and immunotherapy. The combination strategy indeed leads to better outcomes in comparison to RFA alone. In this article, we review the current status of RFA-combined multimodal therapies in the management of HCC.
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Affiliation(s)
- Lumin Chen
- Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jihong Sun
- Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoming Yang
- Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Image-Guided Bio-Molecular Interventions Research, Department of Radiology, University of Washington School of Medicine, Seattle, WA, USA.
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Feng X, Xu R, Du X, Dou K, Qin X, Xu J, Jia W, Wang Z, Zhao H, Yang S, Guo C, Liu T, Ma K. Combination therapy with sorafenib and radiofrequency ablation for BCLC Stage 0-B1 hepatocellular carcinoma: a multicenter retrospective cohort study. Am J Gastroenterol 2014; 109:1891-9. [PMID: 25403366 DOI: 10.1038/ajg.2014.343] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 09/01/2014] [Accepted: 09/02/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The objective of this study was to evaluate the efficacy of combined therapy using Sorafenib and radiofrequency ablation (RFA) with curative intent for all detectable lesions in patients with Barcelona Clinic Liver Cancer (BCLC) Stage 0-B1 hepatocellular carcinoma (HCC). METHODS One hundred and twenty-eight patients with HCC from 12 centers were enrolled in this retrospective study; 64 patients who received Sorafenib plus RFA (Sorafenib-RFA) were compared with a control group treated with RFA alone. The two patient groups were selected with a predefined criterion and matched in terms of their clinical and tumor characteristics at baseline. The primary end point of the study was the incidence of post-RFA HCC recurrence. Secondary end points were overall survival (OS) and treatment toxicity. RESULTS During a median follow-up of 134.1 weeks, 49 patients died and 79 survived. The 1-, 2-, and 3-year cumulative incidences of post-RFA recurrence were 40.5%, 62.9%, and 74.5%, respectively, in the Sorafenib-RFA group, and 62.8%, 85.4%, and 92.7%, respectively, in the RFA group. The 1-, 2-, 3-, and 4-year OS rates were 85.6%, 64.0%, 58.7%, and 50.3%, respectively, in the Sorafenib-RFA group, and 80.7%, 47.2%, 30.9%, and 30.9%, respectively, in the RFA group. Thus, the Sorafenib-RFA group exhibited better survival than the RFA alone group. CONCLUSIONS Combined therapy with Sorafenib-RFA was associated with a lower incidence of post-RFA recurrence and better OS than RFA alone in patients with BCLC Stage 0-B1 HCC. Although these findings suggest that Sorafenib and RFA is safe and effective for the treatment of early HCC, prospective and randomized controlled trials are needed to validate them.
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Affiliation(s)
- Xiaobin Feng
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ruocai Xu
- Hunan Provincial Tumor Hospital, Changsha, China
| | - Xilin Du
- Tangdu Hospital of Forth Military Medical University, Xi'an, China
| | - Kefeng Dou
- Xijing Hospital of Forth Military Medical University, Xi'an, China
| | - Xiao Qin
- The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jun Xu
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | | | - Zhiming Wang
- Xiangya Hospital of Central South University, Changsha, China
| | - Hongzhi Zhao
- Xinqiao Hospital of Third Military Medical University, Chongqing, China
| | - Shufa Yang
- Xinjiang Tumor Hospital, Wulumuqi, China
| | | | - Tianqi Liu
- The People's Hospital of Guangxi Zhuang Zu Autonomous Region, Nanning, China
| | - Kuansheng Ma
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
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Cai H, Kong W, Zhou T, Qiu Y. Radiofrequency ablation versus reresection in treating recurrent hepatocellular carcinoma: a meta-analysis. Medicine (Baltimore) 2014; 93:e122. [PMID: 25396332 PMCID: PMC4616312 DOI: 10.1097/md.0000000000000122] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 08/17/2014] [Accepted: 08/20/2014] [Indexed: 12/17/2022] Open
Abstract
Treatment for recurrent hepatocellular carcinoma (RHCC) remains controversial. This study tried to compare survival benefits between radiofrequency ablation (RFA) and reresection for RHCC patients following curative surgical treatments.Databases were searched for comparative studies published from 2008 to 2014 on RFA versus reresection in treating RHCC. Meta-analysis was performed using a random or fixed-effect model to compare the overall survivals (OSs) and disease-free survivals (DFSs) between RFA and reresection. Begg funnel plot and Egger test were performed to assess the publication bias.Six retrospective comparative studies fulfilled our criteria and were included. For patients with RHCC, RFA was equivalent to reresection in 1-year OSs (odds ratio [OR] 0.86; 95% confidence interval [CI], 0.50-1.49; P = 0.587), 3-year OSs (OR 0.91; 95% CI, 0.64-1.28; P = 0.581), and 5-year OSs (OR 0.97; 95% CI, 0.69-1.36; P = 0.846). However, reresection was superior to RFA in 3-year DFSs (OR 2.25; 95% CI, 1.37-3.68; P = 0.001) and 5-year DFSs (OR 3.70; 95% CI, 1.98-6.93; P = 0.000). The outcome of 1-year DFSs was unstable with statistical heterogeneity among studies included in meta-analysis (I = 77.4%). No evidence of publication bias was found. RFA was considered as a less invasive modality for RHCC patients.RFA achieves comparable OSs as reresection in the treatment of RHCC, with lower postoperative complications.
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Affiliation(s)
- Hao Cai
- Liver Cancer Institute and Zhongshan Hospital (HC); Department of Ultrasound (WK), Zhongshan Hospital, Fudan University, Shanghai; and Department of Hepatobiliary Surgery (TZ, YQ), Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
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12
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Fukuda H, Numata K, Moriya S, Shimoyama Y, Ishii T, Nozaki A, Kondo M, Morimoto M, Maeda S, Sakamaki K, Morita S, Tanaka K. Hepatocellular carcinoma: concomitant sorafenib promotes necrosis after radiofrequency ablation--propensity score matching analysis. Radiology 2014; 272:598-604. [PMID: 24689883 DOI: 10.1148/radiol.14131640] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
PURPOSE To retrospectively compare radiofrequency ablation (RFA) combined with the multikinase inhibitor sorafenib (hereafter, sorafenib-RFA) and RFA alone in the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. Between January 2007 and December 2011, 16 patients (mean age, 72.8 years; age range 52-84 years; 10 men, six women) with HCC tumors less than 3 cm in diameter were included in the sorafenib-RFA group, and 136 patients (mean age, 72.1 years; age range, 51-86 years; 92 men, 44 women) with HCC tumors less than 3 cm in diameter were included in the RFA alone (control) group. Mean diameters of the greatest long-axis dimensions of HCC were 22.8 mm ± 4.6 (standard deviation) in the sorafenib-RFA group and 18.1 mm ± 4.4 in the control group. RFA was performed immediately after the 7-day administration of sorafenib. Propensity score matching analysis was used to adjust for potential biases. RESULTS Fifteen of the 16 patients in the sorafenib-RFA group and 30 of the 136 patients in the control group were selected during propensity score matching. No significant differences between the sorafenib-RFA group (n = 15) and the control group (n = 30) were observed with regard to age, sex, etiology, Child-Pugh class, tumor size, puncture number, needle size, location at the liver margin, or location adjacent to a main vessel. The respective mean diameters of the greatest long- and short-axis dimensions of the RFA-induced ablated area were 46.3 mm ± 10.3 and 33.0 mm ± 6.9 in the sorafenib-RFA group and 32.9 mm ± 7.6 and 25.6 mm ± 5.7 in the control group; both of these dimensions were significantly larger in the sorafenib-RFA group (both P < .001). CONCLUSION Sorafenib-RFA may be superior to standard RFA alone in the treatment of HCC tumors smaller than 3 cm in diameter.
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Affiliation(s)
- Hiroyuki Fukuda
- From the Gastroenterological Center (H.F., K.N., S. Moriya, Y.S., T.I., A.N., M.K., M.M., K.T.), Department of Gastroenterology (S. Maeda), Department of Biostatistics and Epidemiology (K.S., S. Morita), and Clinical Research Coordinating Center (K.S., S. Morita, K.T.), Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan
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Ranieri G, Marech I, Lorusso V, Goffredo V, Paradiso A, Ribatti D, Gadaleta CD. Molecular targeting agents associated with transarterial chemoembolization or radiofrequency ablation in hepatocarcinoma treatment. World J Gastroenterol 2014; 20:486-497. [PMID: 24574717 PMCID: PMC3923023 DOI: 10.3748/wjg.v20.i2.486] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer in the world. According to Barcelona Clinic Liver Cancer modified criteria, patients with early stage disease are candidate to radiofrequency ablation (RFA), while patients with intermediate stage HCC are usually treated by transarterial chemoembolization (TACE). TACE and RFA induce a transient devascularisation effect followed by strong neo-angiogenic stimulus. In fact, after these procedures, it has been demonstrated an up-regulation of pro-angiogenic and growth factors such as vascular endothelial growth factor-A, which might contribute to accelerated progression in patients with incomplete response. Several studies have demonstrated that MAP-kinase and AKT pathways, in addition to neo-angiogenesis, have an important role in the development of HCC. In advanced HCC, anti-angiogenic therapy and tyrosine kinases inhibitors showed potential clinical benefit. Actually, a number of clinical studies are ongoing testing these agents in combination with TACE or RFA. In this paper, we have reviewed the most recent preclinical and clinical results of such trials.
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14
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Radiofrequency ablation suppresses distant tumour growth in a novel rat model of multifocal hepatocellular carcinoma. Clin Sci (Lond) 2013; 126:243-52. [PMID: 23822114 DOI: 10.1042/cs20130089] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
RFA (radiofrequency ablation) is an established therapy for HCC (hepatocellular carcinoma). The multikinase inhibitor sorafenib prolongs survival in advanced HCC. We examined the effects of RFA alone and in combination with sorafenib on a bystanding tumour in a two-tumour rat model of HCC. A total of 80 rats were implanted with two liver tumours and randomized to four treatment groups: vehicle and sham operation (control), sorafenib and sham operation (Sora/Sham), vehicle and RFA (Vh/RFA), and sorafenib and RFA (Sora/RFA) (n=10/group per time point). RFA or sham-operation was performed on the left lobe tumour on day 15. Animals were killed at day 18 and day 30. Non-RFA-targeted right lobe tumours were analysed for angiogenesis, growth factors [HGF (hepatocyte growth factor), EGF (epidermal growth factor) and VEGF (vascular endothelial growth factor)] and infiltrating immune cells (CD3 and CD68). At day 30, the non-RFA-targeted tumours were significantly smaller in all three treatment groups compared with control (Sora/Sham P≤0.0001, Vh/RFA P=0.005 and Sora/RFA P≤0.0001). The smallest tumours were observed in animals treated with a combination of sorafenib and RFA, whereas the size reduction seen in the RFA-only group indicated an RFA-mediated distant suppression of tumour growth. Growth factor measurement revealed transiently decreased EGF levels after RFA (P=0.008), whereas sorafenib treatment decreased HGF levels (P=0.001). MVD (microvessel density) was reduced by sorafenib (P=0.002) despite increased VEGF levels (P≤0.0001). The immune parameters revealed augmented T-cells and IL-10 (interleukin 10) levels in all three treatment groups; sorafenib additionally increased macrophage numbers (P≤0.0001). RFA and sorafenib alone resulted in significant volume reduction of the non-RFA-targeted tumour; this effect was enhanced when both modalities were combined.
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Mollbrink A, Augsten M, Hultcrantz R, Eriksson LC, Stål P. Sorafenib prolongs liver regeneration after hepatic resection in rats. J Surg Res 2013; 184:847-54. [PMID: 23726434 DOI: 10.1016/j.jss.2013.04.062] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 04/09/2013] [Accepted: 04/25/2013] [Indexed: 01/07/2023]
Abstract
BACKGROUND The multikinase inhibitor sorafenib inhibits angiogenesis and tumor cell proliferation. Sorafenib targets signaling pathways involved in liver regeneration. Previous works on regenerating mouse liver show differing results. We asked to which degree different lengths of sorafenib treatment would influence liver regeneration after hepatic resection in rats. METHODS Fischer-344 rats received intragastric injections of sorafenib (5-15 mg/kg/d), underwent a two-thirds partial hepatectomy (PH), and were sacrificed at different time points thereafter. Sorafenib treatment was stopped 0, 3, or 14 d after PH. Serum levels of aminotransferases and labeling indices of S-phase nuclei (bromodeoxyuridine and MIB-5) were analyzed, body and liver weights measured, and levels of phospho-ERK determined by Western blot. RESULTS Sorafenib increased aminotransferases and the number of S-phase nuclei at baseline, but decreased liver weights and levels of phospho-ERK 24 h after PH. The number of S-phase nuclei and mitotic indices decreased 48 h after PH and increased 7 d after PH in animals on sorafenib treatment. Relative liver weights were restored 5 d after PH in control rats, at 7 d in animals receiving sorafenib prior to surgery, at 10 d in rats where sorafenib was stopped 3 d after surgery, and after 14 d in rats on continuous treatment. CONCLUSIONS In this rat model, the regenerating liver adapted to the proliferation-inhibitory effect of sorafenib during continuous treatment. Sorafenib given after hepatic resection did not completely inhibit liver regeneration, but it prolonged the regenerative phase in proportion to the length of treatment.
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Affiliation(s)
- Annelie Mollbrink
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Division of Gastroenterology and Hepatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
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Xu M, Xie XH, Xie XY, Xu ZF, Liu GJ, Zheng YL, Huang GL, Wang W, Zheng SG, Lü MD. Sorafenib suppresses the rapid progress of hepatocellular carcinoma after insufficient radiofrequency ablation therapy: an experiment in vivo. Acta Radiol 2013; 54:199-204. [PMID: 23171528 DOI: 10.1258/ar.2012.120249] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Radiofrequency ablation (RFA) is a widely applied treatment for hepatocellular carcinoma (HCC), but insufficient RFA can promote rapid progression of the residual tumor through the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor A (VEGFA) pathway. Although sorafenib has been successfully applied to advanced HCC, the use of sorafenib in residual tumor cells after RFA has rarely been tested. PURPOSE To evaluate the potential role of sorafenib as an adjunct to RFA to reduce the recurrence rate after insufficient RFA. MATERIAL AND METHODS Xenograft tumors of SMMC 7721 were created by subcutaneously inoculating nude mice with hepatoma cells (5 × 10(6) cells per mouse). Fourteen days after inoculation, all mice were divided into three groups (control group [sham puncture], RFA group, and RFA combined with sorafenib treatment group) with six mice in each group. Each group was given a different treatment procedure. After treatment, the volume of the tumors was calculated from the resected specimens. The mRNA and protein expression of HIF-1α and VEGFA was quantified by real-time PCR and immunohistochemistry analysis. The micro-vessel density (MVD) was determined by CD34 immunohistochemistry. RESULTS Real-time PCR and immunohistochemistry analysis showed that, compared to the RFA group, HIF-1α and VEGFA expression were significantly decreased in the group that received RFA combined with sorafenib treatment (P < 0.05). By comparing the control group with the RFA group, we found that insufficient RFA promoted HIF-1α and VEGFA expression (P < 0.05). Similar results were obtained for MVD expression. Additionally, the combination of RFA with sorafenib therapy resulted in a synergistic reduction in tumor growth compared to insufficient RFA and sham puncture (P < 0.05). CONCLUSION Sorafenib was able to inhibit the expression of HIF-1α and VEGFA, and sorafenib was able to increase time to recurrence when used as an adjunct to RFA.
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Affiliation(s)
- Ming Xu
- Department of Medical Ultrasonics, the First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-Sen University, Guangzhou
| | - Xiao-hua Xie
- Department of Medical Ultrasonics, the First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-Sen University, Guangzhou
| | - Xiao-yan Xie
- Department of Medical Ultrasonics, the First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-Sen University, Guangzhou
| | - Zuo-feng Xu
- Department of Medical Ultrasonics, the First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-Sen University, Guangzhou
| | - Guang-jian Liu
- Department of Medical Ultrasonics, the First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-Sen University, Guangzhou
| | - Yan-ling Zheng
- Department of Medical Ultrasonics, the First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-Sen University, Guangzhou
| | - Guang-liang Huang
- Department of Medical Ultrasonics, the First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-Sen University, Guangzhou
| | - Wei Wang
- Department of Medical Ultrasonics, the First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-Sen University, Guangzhou
| | - Shu-guang Zheng
- Department of Medical Ultrasonics, the First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-Sen University, Guangzhou
| | - Ming-de Lü
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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Thompson SM, Callstrom MR, Knudsen B, Anderson JL, Carter RE, Grande JP, Roberts LR, Woodrum DA. Development and preliminary testing of a translational model of hepatocellular carcinoma for MR imaging and interventional oncologic investigations. J Vasc Interv Radiol 2012; 23:385-95. [PMID: 22265247 PMCID: PMC3904802 DOI: 10.1016/j.jvir.2011.11.018] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 10/28/2011] [Accepted: 11/06/2011] [Indexed: 12/11/2022] Open
Abstract
PURPOSE To develop a translational rat hepatocellular carcinoma (HCC) disease model for magnetic resonance (MR) imaging and image-guided interventional oncologic investigations. MATERIALS AND METHODS Male rats underwent sham control surgery (n = 6), selective bile duct ligation (SBDL; n = 4), or common bile duct ligation (CBDL; n = 6), with procedure optimization in four rats and N1S1 hepatoma cell injection into two or three sites in the livers of 12 rats. All rats subsequently underwent MR imaging to assess tumor establishment and volume. Mesenteric angiography and percutaneous MR-guided laser ablation of the liver were performed in a subgroup of animals (n = 4). Animal weight and liver test results were monitored. After harvesting, the livers were subjected to gross and microscopic analysis. Tumor volume and laboratory parameters were assessed between ligation groups. RESULTS MR imaging demonstrated hyperintense T2 and hypointense T1 lesions with tumor induction in five of 10 (50.0%), seven of eight (87.5%), and 12 of 12 (100%) sites in the control, SBDL, and CBDL groups, respectively. Tumor volumes differed significantly by group (P < .02). Mesenteric angiography demonstrated an enhancing tumor stain. Clinical and laboratory assessment revealed a significant decrease in weight (P = .01) and albumin level (P < .01) and an increase in total bilirubin level (P = .02) in CBDL rats but not SBDL rats (P = 1.0). Histologic examination showed high-grade HCCs with local and vascular invasion within the context of early fibrosis in CBDL and SBDL rats. MR-guided laser ablation generated a 1-2-cm ablation zone with histologic findings consistent with reversible and irreversible injury. CONCLUSIONS A biologically relevant rat HCC disease model has been developed for MR imaging and preliminary interventional oncologic applications.
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MESH Headings
- Animals
- Aortography
- Bile Ducts/surgery
- Carcinoma, Hepatocellular/diagnostic imaging
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/surgery
- Cell Line, Tumor
- Laser Therapy
- Ligation
- Liver Cirrhosis/pathology
- Liver Neoplasms, Experimental/diagnostic imaging
- Liver Neoplasms, Experimental/etiology
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/surgery
- Magnetic Resonance Imaging
- Magnetic Resonance Imaging, Interventional
- Male
- Neoplasm Invasiveness
- Rats
- Rats, Sprague-Dawley
- Time Factors
- Translational Research, Biomedical
- Tumor Burden
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Ahmed M, Moussa M, Goldberg SN. Synergy in cancer treatment between liposomal chemotherapeutics and thermal ablation. Chem Phys Lipids 2011; 165:424-37. [PMID: 22197685 DOI: 10.1016/j.chemphyslip.2011.12.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2011] [Revised: 12/05/2011] [Accepted: 12/06/2011] [Indexed: 01/03/2023]
Abstract
Minimally invasive image-guided tumor ablation using short duration heating via needle-like applicators using energies such as radiofrequency or microwave has seen increasing clinical use to treat focal liver, renal, breast, bone, and lung tumors. Potential benefits of this thermal therapy include reduced morbidity and mortality compared to standard surgical resection and ability to treat non-surgical patients. However, improvements to this technique are required as achieving complete ablation in many cases can be challenging particularly at margins of tumors>3 cm in diameter and adjacent to blood vessels. Thus, one very promising strategy has been to combine thermal tumor ablation with adjuvant nanoparticle-based chemotherapy agents to improve efficiency. Here, we will primarily review principles of thermal ablation to provide a framework for understanding the mechanisms of combination therapy, and review the studies on combination therapy, including presenting preliminary data on the role of such variables as nanoparticle size and thermal dose on improving combination therapy outcome. We will discuss how thermal ablation can also be used to improve overall intratumoral drug accumulation and nanoparticle content release. Finally, in this article we will further describe the appealing off-shoot approach of utilizing thermal ablation techniques not as the primary treatment, but rather, as a means to improve efficiency of intratumoral nanoparticle drug delivery.
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Affiliation(s)
- Muneeb Ahmed
- Minimally Invasive Tumor Therapy Laboratory, Section of Interventional Radiology, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA.
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