Hepatic RF ablation induces not only a local periablational inflammatory zone but also more global proliferative effects on the liver. These IL-6- and/or c-met-mediated changes could potentially account for some of the local and distant tumor recurrence observed after treatment.

PurposeRadiofrequency thermal ablation (RFA) of hepatic and renal tumors can be accompanied by non-desired tumorigenesis in residual, untreated tumor. Here, we studied the use of micelle-encapsulated siRNA to suppress IL-6-mediated local and systemic secondary effects of RFA.MethodsWe compared standardized hepatic or renal RFA (laparotomy, 1 cm active tip at 70±2°C for 5 min) and sham procedures without and with administration of 150nm micelle-like nanoparticle (MNP) anti-IL6 siRNA (DOPE-PEI conjugates, single IP dose 15 min post-RFA, C57Bl mouse:3.5 ug/100ml, Fisher 344 rat: 20ug/200ul), RFA/scrambled siRNA, and RFA/empty MNPs. Outcome measures included: local periablational cellular infiltration (α-SMA+ stellate cells), regional hepatocyte proliferation, serum/tissue IL-6 and VEGF levels at 6-72hr, and distant tumor growth, tumor proliferation (Ki-67) and microvascular density (MVD, CD34) in subcutaneous R3230 and MATBIII breast adenocarcinoma models at 7 days.ResultsFor liver RFA, adjuvant MNP anti-IL6 siRNA reduced RFA-induced increases in tissue IL-6 levels, α-SMA+ stellate cell infiltration, and regional hepatocyte proliferation to baseline (p<0.04, all comparisons). Moreover, adjuvant MNP anti-IL6- siRNA suppressed increased distant tumor growth and Ki-67 observed in R3230 and MATBIII tumors post hepatic RFA (p<0.01). Anti-IL6 siRNA also reduced RFA-induced elevation in VEGF and tumor MVD (p<0.01). Likewise, renal RFA-induced increases in serum IL-6 levels and distant R3230 tumor growth was suppressed with anti-IL6 siRNA (p<0.01).ConclusionsAdjuvant nanoparticle-encapsulated siRNA against IL-6 can be used to modulate local and regional effects of hepatic RFA to block potential unwanted pro-oncogenic effects of hepatic or renal RFA on distant tumor.

Purpose To determine whether variable hepatic microwave ablation (MWA) can induce local inflammation and distant pro-oncogenic effects compared with hepatic radiofrequency ablation (RFA) in an animal model. Materials and Methods In this institutional Animal Care and Use Committee-approved study, F344 rats (150 gm, n = 96) with subcutaneous R3230 breast adenocarcinoma tumors had normal non-tumor-bearing liver treated with RFA (70°C × 5 minutes), rapid higher-power MWA (20 W × 15 seconds), slower lower-power MWA (5 W × 2 minutes), or a sham procedure (needle placement without energy) and were sacrificed at 6 hours to 7 days (four time points; six animals per arm per time point). Ablation settings produced 11.4 mm ± 0.8 of coagulation for all groups. Distant tumor growth rates were determined to 7 days after treatment. Liver heat shock protein (HSP) 70 levels (at 72 hours) and macrophages (CD68 at 7 days), tumor proliferative indexes (Ki-67 and CD34 at 7 days), and serum and tissue levels of interleukin 6 (IL-6) at 6 hours, hepatocyte growth factor (HGF) at 72 hours, and vascular endothelial growth factor (VEGF) at 72 hours after ablation were assessed. All data were expressed as means ± standard deviations and were compared by using two-tailed t tests and analysis of variance for selected group comparisons. Linear regression analysis of tumor growth curves was used to determine pre- and posttreatment growth curves on a per-tumor basis. Results At 7 days, hepatic ablations with 5-W MWA and RFA increased distant tumor size compared with 20-W MWA and the sham procedure (5-W MWA: 16.3 mm ± 1.1 and RFA: 16.3 mm ± 0.9 vs sham: 13.6 mm ± 1.3, P < .01, and 20-W MWA: 14.6 mm ± 0.9, P < .05). RFA and 5-W MWA increased postablation tumor growth rates compared with the 20-W MWA and sham arms (preablation growth rates range for all arms: 0.60-0.64 mm/d; postablation: RFA: 0.91 mm/d ± 0.11, 5-W MWA: 0.91 mm/d ± 0.14, P < .01 vs pretreatment; 20-W MWA: 0.69 mm/d ± 0.07, sham: 0.56 mm/d ± 1.15; P = .48 and .65, respectively). Tumor proliferation (Ki-67 percentage) was increased for 5-W MWA (82% ± 5) and RFA (79% ± 5), followed by 20-W MWA (65% ± 2), compared with sham (49% ± 5, P < .01). Likewise, distant tumor microvascular density was greater for 5-W MWA and RFA (P < .01 vs 20-W MWA and sham). Lower-energy MWA and RFA also resulted in increased HSP 70 expression and macrophages in the periablational rim (P < .05). Last, IL-6, HGF, and VEGF elevations were seen in 5-W MWA and RFA compared with 20-W MWA and sham (P < .05). Conclusion Although hepatic MWA can incite periablational inflammation and increased distant tumor growth similar to RFA in an animal tumor model, higher-power, faster heating protocols may potentially mitigate such undesired effects. RSNA, 2016.

Purpose:To compare hepatocellular carcinoma (HCC) development after radiofrequency (RF) ablation, partial surgical hepatectomy, and a sham operation and to inhibit HCC recurrence after RF ablation in a mouse model of spontaneously forming HCC in the setting of chronic inflammation (ie, the MDR2 knockout model). Materials and Methods:Animal experiments were performed according to an approved animal care committee protocol. The authors compared the survival of MDR2 knockout mice (an inflammation-induced HCC model) that underwent RF ablation, 35% partial hepatectomy (ie, left lobectomy), or a sham operation (controls) by using Kaplan-Meier survival curve analysis. Tumor load and tumor frequency in mice that underwent sham operation were further compared with those of mice treated with RF ablation at 1 month after therapy by using a two-tailed Student t test. Liver slices from mice treated with RF ablation were stained for a2smooth muscle actin and Ki-67 to establish the role of liver regeneration in the tumorigenic effect of RF ablation. Finally, tumor load and tumor incidence were evaluated in mice treated with a c-met inhibitor after RF ablation by using the Mann-Whitney U test. Results:Ablation of 3.5% 6 0.02 of the MDR2 knockout mice liver induced increased tumor load (P = .007) and reduced survival (P = .03) in comparison to that of controls, with no significant difference to the 10-fold volume removal of partial hepatectomy. Seven days after RF treatment, the border zone of the coagulation zone was surrounded by a2smooth muscle actin-positive activated myofibroblasts. A significant elevation of hepatocyte proliferation was also seen 7 days after RF ablation in the distant liver (ablated lobe: P = .003; untreated lobe: P = .02). A c-met inhibitor significantly attenuated HCC development in MDR2 knockout mice treated with RF ablation (P = .001). Conclusion:Liver regeneration induced by RF ablation facilitates cmet/hepatocyte growth factor axis-dependent HCC tumor formation after treatment in the MDR2 knockout model. Blockage of the c-met/hepatocyte growth factor axis attenuates HCC recurrence, raising the potential for therapeutic intervention to reverse this potentially deleterious tumorigenic effect.q RSNA, 2015

To compare hepatocellular carcinoma (HCC) development after radiofrequency (RF) ablation, partial surgical hepatectomy, and a sham operation and to inhibit HCC recurrence after RF ablation in a mouse model of spontaneously forming HCC in the setting of chronic inflammation (ie, the MDR2 knockout model). Materials and Methods: Animal experiments were performed according to an approved animal care committee protocol. The authors compared the survival of MDR2 knockout mice (an inflammation-induced HCC model) that underwent RF ablation, 35% partial hepatectomy (ie, left lobectomy), or a sham operation (controls) by using Kaplan-Meier survival curve analysis. Tumor load and tumor frequency in mice that underwent sham operation were further compared with those of mice treated with RF ablation at 1 month after therapy by using a two-tailed Student t test. Liver slices from mice treated with RF ablation were stained for a2smooth muscle actin and Ki-67 to establish the role of liver regeneration in the tumorigenic effect of RF ablation. Finally, tumor load and tumor incidence were evaluated in mice treated with a c-met inhibitor after RF ablation by using the Mann-Whitney U test. Results: Ablation of 3.5% 6 0.02 of the MDR2 knockout mice liver induced increased tumor load (P = .007) and reduced survival (P = .03) in comparison to that of controls, with no significant difference to the 10-fold volume removal of partial hepatectomy. Seven days after RF treatment, the border zone of the coagulation zone was surrounded by a2smooth muscle actin-positive activated myofibroblasts. A significant elevation of hepatocyte proliferation was also seen 7 days after RF ablation in the distant liver (ablated lobe: P = .003; untreated lobe: P = .02). A c-met inhibitor significantly attenuated HCC development in MDR2 knockout mice treated with RF ablation (P = .001). Conclusion: Liver regeneration induced by RF ablation facilitates cmet/hepatocyte growth factor axis-dependent HCC tumor formation after treatment in the MDR2 knockout model. Blockage of the c-met/hepatocyte growth factor axis attenuates HCC recurrence, raising the potential for therapeutic intervention to reverse this potentially deleterious tumorigenic effect.