Heating technology for malignant tumors: a review

The therapeutic application of heat is very effective in cancer treatment. Both hyperthermia, i.e., heating to 39-45 degrees C to induce sensitization to radiotherapy and chemotherapy, and thermal ablation, where temperatures beyond 50 degrees C destroy tumor cells directly are frequently applied in the clinic. Achievement of an effective treatment requires high quality heating equipment, precise thermal dosimetry, and adequate quality assurance. Several types of devices, antennas and heating or power delivery systems have been proposed and developed in recent decades. These vary considerably in technique, heating depth, ability to focus, and in the size of the heating focus. Clinically used heating techniques involve electromagnetic and ultrasonic heating, hyperthermic perfusion and conductive heating. Depending on clinical objectives and available technology, thermal therapies can be subdivided into three broad categories: local, locoregional, or whole body heating. Clinically used local heating techniques include interstitial hyperthermia and ablation, high intensity focused ultrasound (HIFU), scanned focused ultrasound (SFUS), electroporation, nanoparticle heating, intraluminal heating and superficial heating. Locoregional heating techniques include phased array systems, capacitive systems and isolated perfusion. Whole body techniques focus on prevention of heat loss supplemented with energy deposition in the body, e.g., by infrared radiation. This review presents an overview of clinical hyperthermia and ablation devices used for local, locoregional, and whole body therapy. Proven and experimental clinical applications of thermal ablation and hyperthermia are listed. Methods for temperature measurement and the role of treatment planning to control treatments are discussed briefly, as well as future perspectives for heating technology for the treatment of tumors

Relevance of Rabbit VX2 Tumor Model for Studies on Human Hepatocellular Carcinoma: A MicroRNA-Based Study

MicroRNAs are small (~22 nt), noncoding RNA molecules that have critical cellular functions in proliferation, differentiation, angiogenesis and apoptosis. miRNA expression profiling has been used to create signatures of solid tumors and, in many cases, it has been shown to correlate with the severity of the disease. The rabbit VX2 tumor model has been used widely to study a number of human cancers. Our objective in this study is to generate an miRNA signature of the VX2 tumor and to identify miRNAs that are highly expressed in this aggressive tumor. In this study, we performed miRNA profiling of the rabbit VX2 tumor using a microarray that has probes for 1292 unique miRNAs. Their expression in tumor samples was quantified and analyzed. We found that 35 miRNAs were significantly up-regulated in the VX2 tumor. Among these, 13 human miRNAs and eight members of the let-7 family were previously identified in cancers. In addition, we show that the expression of three miRNAs (miR-923, miR-1275, and miR-1308) is novel for the rabbit VX2 tumor, and their expression was not previously shown to be associated with any type of cancer. For the first time, we show the miRNA signature profile for a solid tumor in a rabbit model. miRNAs highly expressed in the VX2 tumor may serve as novel candidates for molecular biomarkers and as potential drug targets

Image-guided chemistry altering biology: An in vivo study of thermoembolization.

RATIONALE:Advances in image-guided drug delivery for liver cancer have shown a significant survival benefit. However, incomplete treatment is common and residual disease is often found in explanted liver specimens. In addition, the need to treat a malignancy from multiple mechanisms at the same time for optimal outcomes is becoming more widely appreciated. To address this, we hypothesized that an exothermic chemical reaction could be performed in situ. Such a strategy could in principle combine several angles of attack, including ischemia, hyperthermia, acidic protein denaturation, and metabolic modulation of the local environment. METHODS:The University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee approved this study. Outbred swine (25-35 kg, 5 control and 5 experimental) were treated under general anesthesia. Embolization was performed with coaxial microcatheter technique in a segmental hepatic arterial branch using either ethiodized oil as control or with thermoembolic solutionBlood samples were obtained before, immediately after, and the day following the procedure just before CT scans and euthanasia. Livers were explanted and samples were obtained for histologic analysis. RESULTS:All animals survived the procedure and laboratory values of the control and experimental groups remained within normal limits. The control group had a diffuse or cloudy pattern of attenuation on follow-up CT scan the day after, consistent with gradual antegrade sinusoidal transit of the embolic material. The experimental group had clearly defined vascular casts with some degree of peripheral involvement. At histology, the control group samples had the appearance of normal liver, whereas the experimental group had coagulative necrosis in small pale, punctate areas extending several hundred microns away from the treated vessels and a brisk inflammatory response just outside the margins. CONCLUSION:In situ chemistry via thermoembolization shows early promise as a fundamentally new tactic for image-guided therapy of solid tumors

Histological Correlation for Radiofrequency and Microwave Ablation in the Local Control of Hepatocellular Carcinoma (HCC) before Liver Transplantation: A Comprehensive Review

Radiofrequency ablation (RFA) and microwave ablation (MWA) are the most widely studied and applied ablation techniques for treating primary and secondary liver tumors. These techniques are considered curative for small hepatic tumors, with post-ablation outcomes most commonly assessed by an imaging follow up. However, there is increasing evidence of a discrepancy between radiological and pathological findings when ablated lesions are evaluated following liver resection or liver transplantation. A comprehensive review of the available literature reporting the complete pathological response (cPR) following RFA and MWA was performed to estimate the success rate and identify the factors associated with treatment failure. Following RFA, cPR is reported in 26–96% of tumors compared to 57–95% with MWA. Larger tumor size and vessels larger than 3 mm adjacent to the treated tumor are the most important factors identified by previous studies associated with viable residual tumors after RFA. Correlating post-ablation radiological studies with pathological findings shows that computed tomography (CT) and magnetic resonance imaging (MRI) have low sensitivity but high specificity for detecting residual viable or recurrent hepatocellular carcinoma (HCC) tumors. There are promising recent reports combining multiprobe ablation techniques with three-dimensional treatment planning software and stereotactic-aiming instrumentation to achieve more than 90% cPR in both small and large HCC tumors. In conclusion, the reported success for achieving cPR in HCC following RFA and MWA is highly variable in different studies and decreases with increasing lesion size and unfavorable tumor characteristics. Very few studies have reported a high rate of cPR. As these studies are single-center and retrospective, they need to be further validated and reproduced in other clinical settings

Gross pathology of section of treated lobe of liver.

<p>At this early stage (24 h after treatment) treated areas appear as small areas of light red to orange color (blue arrows) against the background of red parenchyma.</p

Histology of thermoembolization at 24 hours post-procedure with low and high power views.

<p>(A) Perivascular distribution of coagulative necrosis is clearly demonstrated with dense inflammatory infiltrate at margins (yellow arrow). (B) Magnification view of lesion in A: note the distance the necrosis extends from the vessel lumen and the amount of necrosis, particularly in view of the small dose employed (400 μL). Localized lymphocytic infiltrate and hemorrhage are present surrounding the lesions. Bar = 1000 μm (L) and 600 μm (R).</p

Liver function laboratory results.

<p>Liver function laboratory results.</p

Illustration of electrophilic hydrolysis with water as the nucleophile and sequence of events thereafter.

<p>The water attacks and ultimately displaces the chloride ion on the carbonyl carbon, releasing -93 kJ/Mol of thermal energy [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200471#pone.0200471.ref038" target="_blank">38</a>]. At the same time, it generates HCl and the carboxylic acid. The two chlorine atoms on dichloroacetic acid lower the pKa to 1.26 making dichloroacetic acid also a strong acid. After protonation of a substrate occurs, the dichloroacetate anion remains and has intrinsic pharmacologic activity. Thus, heat, acid, drug, and ischemia are all combined in a single stroke, overwhelming cells and resulting in localized cell death.</p

Control arm using vehicle (ethiodized oil) alone.

<p>Non-contrast CT image obtained 24 h post embolization (A) in situ and (B) reformatted showing distribution of embolic agent. Note contrast with experimental agent, with diffuse, cloud-like distal distribution pattern of liquid embolic and absence of linear vascular structures. This corresponds to movement out to the sinusoidal level. The pattern indicates that stasis did not occur in this arm of the study and thus minimal or no necrosis would be expected. This was confirmed at histology. In clinical practice, this pattern disappears over 3–4 weeks and is not apparent on follow-up scans.</p