Percutaneous radiofrequency ablation of HCC: reduced ablation duration and increased ablation size using single, internally cooled electrodes with an optimized pulsing algorithm

Purpose To assess the use of optimized radiofrequency (RF) to achieve larger, spherical ablation volumes with short application duration for hepatocellular carcinoma (HCC). Materials and methods Twenty-two patients (M:F = 17:5, median age 69.6 year, range 63–88) with 28 HCCs due to HCV + liver cirrhosis underwent RFA. 20/28 (71.4%) were tumors ≤3cm diameter, and 8/28 (28.6%) ranged from 3.2 to 4.2 cm. RF was applied using up to 2500mA via an optimized pulsing algorithm with real-time ultrasound monitoring to detect hyperechogenic changes. Single insertions of an internally cooled electrode were performed using exposed tips of 2 or 3 cm for 13 HCCs and 4 cm for 15 HCCs. All patients were followed-up for a minimum of 5 years with contrast-enhanced computed tomography (CECT). Results Technical success was achieved without adverse events in all cases. The mean ablation time was 8.5 ± 2.6 min. In 21/28 (75%), ablation duration ranged from 3 to 9 min, with 12 min duration applied in only 7/28 (25%). Mean coagulation diameters were 2.4 ± 0.14, 3.3 ± 0.62, and 4.4 ± 1.0, for 2, 3 and 4 cm electrodes, respectively (p 3 cm tumors developed local progression. One patient had multifocal disease with no local progression. Conclusion Efficient delivery of RF energy can considerably decrease the ablation time in many instances while achieving larger, relatively spherical, and reproducible areas of ablation with extremely low rates of local tumor progression and adverse events

Nanodrug-Enhanced Radiofrequency Tumor Ablation: Effect of Micellar or Liposomal Carrier on Drug Delivery and Treatment Efficacy

Purpose To determine the effect of different drug-loaded nanocarriers (micelles and liposomes) on delivery and treatment efficacy for radiofrequency ablation (RFA) combined with nanodrugs. Materials/Methods Fischer 344 rats were used (n = 196). First, single subcutaneous R3230 tumors or normal liver underwent RFA followed by immediate administration of IV fluorescent beads (20, 100, and 500 nm), with fluorescent intensity measured at 4–24 hr. Next, to study carrier type on drug efficiency, RFA was combined with micellar (20 nm) or liposomal (100 nm) preparations of doxorubicin (Dox; targeting HIF-1α) or quercetin (Qu; targeting HSP70). Animals received RFA alone, RFA with Lipo-Dox or Mic-Dox (1 mg IV, 15 min post-RFA), and RFA with Lipo-Qu or Mic-Qu given 24 hr pre- or 15 min post-RFA (0.3 mg IV). Tumor coagulation and HIF-1α orHSP70 expression were assessed 24 hr post-RFA. Third, the effect of RFA combined with IV Lipo-Dox, Mic-Dox, Lipo-Qu, or Mic-Qu (15 min post-RFA) compared to RFA alone on tumor growth and animal endpoint survival was evaluated. Finally, drug uptake was compared between RFA/Lipo-Dox and RFA/Mic-Dox at 4–72 hr. Results: Smaller 20 nm beads had greater deposition and deeper tissue penetration in both tumor (100 nm/500 nm) and liver (100 nm) (p<0.05). Mic-Dox and Mic-Qu suppressed periablational HIF-1α or HSP70 rim thickness more than liposomal preparations (p<0.05). RFA/Mic-Dox had greater early (4 hr) intratumoral doxorubicin, but RFA/Lipo-Dox had progressively higher intratumoral doxorubicin at 24–72 hr post-RFA (p<0.04). No difference in tumor growth and survival was seen between RFA/Lipo-Qu and RFA/Mic-Qu. Yet, RFA/Lipo-Dox led to greater animal endpoint survival compared to RFA/Mic-Dox (p<0.03). Conclusion: With RF ablation, smaller particle micelles have superior penetration and more effective local molecular modulation. However, larger long-circulating liposomal carriers can result in greater intratumoral drug accumulation over time and reduced tumor growth. Accordingly, different carriers provide specific advantages, which should be considered when formulating optimal combination therapies

Tissue shrinkage in microwave ablation of liver: an ex vivo predictive model

The aim of this study was to develop a predictive model of the shrinkage of liver tissues in microwave ablation.Thirty-seven cuboid specimens of ex vivo bovine liver of size ranging from 2 cm to 8 cm were heated exploiting different techniques: 1) using a microwave oven (2.45 GHz) operated at 420 W, 500 W and 700 W for 8 to 20 min, achieving complete carbonisation of the specimens, 2) using a radiofrequency ablation apparatus (450 kHz) operated at 70 W for a time ranging from 6 to 7.5 min obtaining white coagulation of the specimens, and 3) using a microwave (2.45 GHz) ablation apparatus operated at 60 W for 10 min. Measurements of specimen dimensions, carbonised and coagulated regions were performed using a ruler with an accuracy of 1 mm. Based on the results of the first two experiments a predictive model for the contraction of liver tissue from microwave ablation was constructed and compared to the result of the third experiment.For carbonised tissue, a linear contraction of 31 ± 6% was obtained independently of the heating source, power and operation time. Radiofrequency experiments determined that the average percentage linear contraction of white coagulated tissue was 12 ± 5%. The average accuracy of our model was determined to be 3 mm (5%).The proposed model allows the prediction of the shrinkage of liver tissues upon microwave ablation given the extension of the carbonised and coagulated zones. This may be useful in helping to predict whether sufficient tissue volume is ablated in clinical practice

A novel software platform for volumetric assessment of ablation completeness

Purpose: To retrospectively evaluate the accuracy of a novel software platform for assessing completeness of percutaneous thermal ablations. Materials & methods: Ninety hepatocellular carcinomas (HCCs) in 50 patients receiving percutaneous ultrasound-guided microwave ablation (MWA) that resulted in apparent technical success at 24-h post-ablation computed tomography (CT) and with ≥1-year imaging follow-up were randomly selected from a 320 HCC ablation database (2010–2016). Using a novel volumetric registration software, pre-ablation CT volumes of the HCCs without and with the addition of a 5 mm safety margin, and corresponding post-ablation necrosis volumes were segmented, co-registered and overlapped. These were compared to visual side-by-side inspection of axial images. Results: At 1-year follow-up, CT showed absence of local tumor progression (LTP) in 69/90 (76.7%) cases and LTP in 21/90 (23.3%). For HCCs classified by the software as "incomplete tumor treatments", LTP developed in 13/17 (76.5%) and all 13 (100%) of these LTPs occurred exactly where residual non-ablated tumor was identified by retrospective software analysis. HCCs classified as "complete ablation with <100% 5 mm ablative margins" had LTP in 8/49 (16.3%), while none of 24 HCCs with "complete ablation including 100% 5 mm ablative margins" had LTP. Differences in LTP between both partially ablated HCCs vs completely ablated HCCs, and ablated HCCs with <100% vs with 100% 5 mm margins were statistically significant (p < .0001 and p = .036, respectively). Thus, 13/21 (61.9%) incomplete tumor treatments could have been detected immediately, were the software available at the time of ablation. Conclusions: A novel software platform for volumetric assessment of ablation completeness may increase the detection of incompletely ablated tumors, thereby holding the potential to avoid subsequent recurrences

Microwave ablation of primary and secondary liver tumours: ex vivo, in vivo, and clinical characterisation.

The aim of this study was to compare the performance of a microwave ablation (MWA) apparatus in preclinical and clinical settings.The same commercial 2.45 GHz MWA apparatus was used throughout this study. In total 108 ablations at powers ranging from 20 to 130 W and lasting from 3 to 30 min were obtained on ex vivo bovine liver; 28 ablations at 60 W, 80 W and 100 W lasting 5 and 10 min were then obtained in an in vivo swine model. Finally, 32 hepatocellular carcinomas (HCCs) and 19 liver metastases in 46 patients were treated percutaneously by administering 60 W for either 5 or 10 min. The treatment outcome was characterised in terms of maximum longitudinal and transversal axis of the induced ablation zone.Ex vivo ablation volumes increased linearly with deposited energy (rFor the selected MW ablation device, ex vivo data on bovine liver was more predictive of the actual clinical performance on liver malignancies than an in vivo porcine model. Equivalent MW treatments yielded a significantly different response for HCC and metastases at higher deposited energy, suggesting that outcomes are not only device-specific but must also be characterised on a tissue-by-tissue basis

High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model.</p> <p>Methods</p> <p>Mice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10.</p> <p>Results</p> <p>Tumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion.</p> <p>Conclusions</p> <p>A modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.</p

Cox-2 Inhibition Enhances the Activity of Sunitinib in Human Renal Cell Carcinoma Xenografts

Background: Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su. Methods: COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared. Results: COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy. Conclusion: COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC

Elastin-specific MRI of extracellular matrix-remodelling following hepatic radiofrequency-ablation in a VX2 liver tumor model

Hepatic radiofrequency ablation (RFA) induces a drastic alteration of the biomechanical environment in the peritumoral liver tissue. The resulting increase in matrix stiffness has been shown to significantly influence carcinogenesis and cancer progression after focal RF ablation. To investigate the potential of an elastin-specific MR agent (ESMA) for the assessment of extracellular matrix (ECM) remodeling in the periablational rim following RFA in a VX2 rabbit liver tumor-model, twelve New-Zealand-White-rabbits were implanted in the left liver lobe with VX2 tumor chunks from donor animals. RFA of tumors was performed using a perfused RF needle-applicator with a mean tip temperature of 70 degrees C. Animals were randomized into four groups for MR imaging and scanned at four different time points following RFA (week 0 [baseline], week 1, week 2 and week 3 after RFA), followed by sacrifice and histopathological analysis. ESMA-enhanced MR imaging was used to assess ECM remodeling. Gadobutrol was used as a third-space control agent. Molecular MR imaging using an elastin-specific probe demonstrated a progressive increase in contrast-to-noise ratio (CNR) (week 3: ESMA: 28.1 +/- 6.0; gadobutrol: 3.5 +/- 2.0), enabling non-invasive imaging of the peritumoral zone with high spatial-resolution, and accurate assessment of elastin deposition in the periablational rim. In vivo CNR correlated with ex vivo histomorphometry (ElasticaVanGiesson-stain, y=1.2x - 1.8, R-2=0.89, p<0.05) and gadolinium concentrations at inductively coupled mass spectroscopy (ICP-MS, y=0.04x+1.2, R-2=0.95, p<0.05). Laser-ICP-MS confirmed colocalization of elastin-specific probe with elastic fibers. Following thermal ablation, molecular imaging using an elastin-specific MR probe is feasible and provides a quantifiable biomarker for the assessment of the ablation-induced remodeling of the ECM in the periablational rim

Early monocyte response following local ablation in hepatocellular carcinoma

Local ablative therapies are established treatment modalities in the treatment of early- and intermediate-stage hepatocellular carcinoma (HCC). Systemic effects of local ablation on circulating immune cells may contribute to patients’ response. Depending on their activation, myeloid cells are able to trigger HCC progression as well as to support anti-tumor immunity. Certain priming of monocytes may already occur while still in the circulation. By using flow cytometry, we analyzed peripheral blood monocyte cell populations from a prospective clinical trial cohort of 21 HCC patients following interstitial brachytherapy (IBT) or radiofrequency ablation (RFA) and investigated alterations in the composition of monocyte subpopulations and monocytic myeloid-derived suppressor cells (mMDSCs) as well as receptors involved in orchestrating monocyte function. We discovered that mMDSC levels increased following both IBT and RFA in virtually all patients. Furthermore, we identified varying alterations in the level of monocyte subpopulations following radiation compared to RFA. (A) Liquid biopsy liquid biopsy of circulating monocytes in the future may provide information on the inflammatory response towards local ablation as part of an orchestrated immune response