The Accumulation and Effects of Liposomal Doxorubicin in Tissues Treated by Radiofrequency Ablation and Irreversible Electroporation in Liver: In Vivo Experimental Study on Porcine Models.

PURPOSE: To compare the accumulation and effect of liposomal doxorubicin in liver tissue treated by radiofrequency ablation (RFA) and irreversible electroporation (IRE) in in vivo porcine models. MATERIALS AND METHODS: Sixteen RFA and 16 IRE procedures were performed in healthy liver of two groups of three pigs. Multi-tined RFA parameters included: 100 W, target temperature 105°C for 7 min. 100 IRE pulses were delivered using two monopolar electrodes at 2250 V, 1 Hz, for 100 µsec. For each group, two pigs received 50 mg liposomal doxorubicin (0.5 mg/kg) as a drip infusion during ablation procedure, with one pig serving as control. Samples were harvested from the central and peripheral zones of the ablation at 24 and 72 h. Immunohistochemical analysis to evaluate the degree of cellular stress, DNA damage, and degree of apoptosis was performed. These and the ablation sizes were compared. Doxorubicin concentrations were also analyzed using fluorescence photometry of homogenized tissue. RESULTS: RFA treatment zones created with concomitant administration of doxorubicin at 24 h were significantly larger than controls (2.5 ± 0.3 cm vs. 2.2 ± 0.2 cm; p = 0.04). By contrast, IRE treatment zones were negatively influenced by chemotherapy (2.2 ± 0.4 cm vs. 2.6 ± 0.4 cm; p = 0.05). At 24 h, doxorubicin concentrations in peripheral and central zones of RFA were significantly increased in comparison with untreated parenchyma (0.431 ± 0.078 µg/g and 0.314 ± 0.055 µg/g vs. 0.18 ± 0.012 µg/g; p < 0.05). Doxorubicin concentrations in IRE zones were not significantly different from untreated liver (0.191 ± 0.049 µg/g and 0.210 ± 0.049 µg/g vs. 0.18 ± 0.012 µg/g). CONCLUSIONS: Whereas there is an increased accumulation of periprocedural doxorubicin and an associated increase in ablation zone following RFA, a contrary effect is noted with IRE. These discrepant findings suggest that different mechanisms and synergies will need to be considered in order to select optimal adjuvants for different classes of ablation devices.

[PERCUTANEOUS TREATMENT OF SMALL RENAL TUMORS BY THERMAL ABLATION].

INTRODUCTION: Kidney cancer accounts for approximately 2-3 % of all types of cancers. Renal tumors prevalence and especially the prevalence of small renal tumors, is on the rise. About half of the tumors currently diagnosed are smaller than 4 cm. Minimally invasive methods of radiofrequency ablation technology were recently developed for the treatment of small renal tumors and are characterized by reducing the surgical and anesthetic risk. The ablation is performed with a percutaneous approach guided by ultrasound, CT or MRI. We reviewed the results of this treatment. METHODS: A total of 75 patients with a mean age of 69.5 years (27 - 90) were treated using RF during the period 2007-2014. The average tumor diameter was 28.4 mm (11-58 mm); 40 tumors were exophytic and 30 were central. Monitoring protocol after treatment included imaging after 1, 3, 6, 12 months subsequent to treatment and later annually; median follow-up time was 21 months (1 - 97). RESULTS: Evidence of tumor recurrence was observed in 9 patients (11.4%); 8 were treated successfully by another RF session. Cases in which recurrence was observed were characterized by a tumor larger than 30 mm (5/9) and adjacent to renal cysts (3/9); 5 of the lesions were central (endophytic) (P=0.5). One patient died due to metastatic RCC and a metastatic disease developed in two additional patients who died of other causes. CONCLUSIONS: It is possible to destroy most of the small renal tumors by RF ablation. When the tumor size is up to 30 mm, a 94% long-term cure may be reached. In the event of renewed growth of the tumor, the treatment can be repeated with good results. In light of short-term experience, it is recommended to limit this treatment to older patients, with a short life expectancy or when anesthetic risks prohibit surgery.

Thermal ablation of colorectal liver metastases: a position paper by an international panel of ablation experts, The Interventional Oncology Sans Frontières meeting 2013.

OBJECTIVES: Previous attempts at meta-analysis and systematic review have not provided clear recommendations for the clinical application of thermal ablation in metastatic colorectal cancer. Many authors believe that the probability of gathering randomised controlled trial (RCT) data is low. Our aim is to provide a consensus document making recommendations on the appropriate application of thermal ablation in patients with colorectal liver metastases. METHODS: This consensus paper was discussed by an expert panel at The Interventional Oncology Sans Frontières 2013. A literature review was presented. Tumour characteristics, ablation technique and different clinical applications were considered and the level of consensus was documented. RESULTS: Specific recommendations are made with regard to metastasis size, number, and location and ablation technique. Mean 31 % 5-year survival post-ablation in selected patients has resulted in acceptance of this therapy for those with technically inoperable but limited liver disease and those with limited liver reserve or co-morbidities that render them inoperable. CONCLUSIONS: In the absence of RCT data, it is our aim that this consensus document will facilitate judicious selection of the patients most likely to benefit from thermal ablation and provide a unified interventional oncological perspective for the use of this technology. KEY POINTS: • Best results require due consideration of tumour size, number, volume and location. • Ablation technology, imaging guidance and intra-procedural imaging assessment must be optimised. • Accepted applications include inoperable disease due to tumour distribution or inadequate liver reserve. • Other current indications include concurrent co-morbidity, patient choice and the test-of-time approach. • Future applications may include resectable disease, e.g. for small solitary tumours.

Humoral bone morphogenetic protein 2 is sufficient for inducing breast cancer microcalcification.

Microcalcifications are an important diagnostic marker for breast cancer on mammograms, yet the mechanism of their formation is poorly understood. Indeed, there is presently no short-latency, high-yield, syngeneic rodent model of the process. Bone morphogenetic protein 2 (BMP-2) is a key mediator of physiologic bone formation and pathologic vasculature calcification, but its role in breast cancer microcalcification is unknown. In this study, R3230 rat breast tumors were adapted to cell culture, transduced with adenoviral BMP-2, and inoculated into a syngeneic host. Tumor growth and calcium salt deposition were quantified in living animals over time using micro-computed tomography and probed chemically using near-infrared fluorescence. Plasma BMP-2 levels were quantified over time by enzyme-linked immunosorbent assay. Within 3 weeks, 100% of the breast tumors developed microcalcifications, which were absent from all normal tissues. Importantly, when two tumors were initiated in a single host, the ipsilateral tumor expressing BMP-2 was able to induce microcalcification in the contralateral tumor that was not expressing BMP-2, suggesting that BMP-2 can act humorally. Taken together, we describe the first reproducible rodent model of breast cancer microcalcification, prove that BMP-2 expression is sufficient for initiating the process, and lay the foundation for a new generation of targeted diagnostic agents.