SonoKnife for ablation of neck tissue: in vivo verification of a computer layered medium model.

PURPOSE: This study aimed to determine which treatment parameters of the SonoKnife device can be used to safely and effectively perform non-invasive thermal ablation of subcutaneous tissue. METHODS: A three-dimensional computational layered medium model was constructed to simulate thermal ablation treatment of the SonoKnife device. The acoustic and thermal fields were calculated with the Fast Object-Oriented C++ Ultrasound-Simulator software and a finite difference code, respectively. Subcutaneous tissue was represented as layers of skin, fat and muscle. The simulations were conducted for ultrasound frequencies of 1 or 3.5 MHz. The thermal dose model was used to predict the size and location of the ablated regions. The computer simulations were verified by using the SonoKnife to perform subcutaneous ablations in the neck area of healthy pigs, in vivo. Triphenyltetrazolium chloride viability stain was used to differentiate viable tissue from ablated regions ex vivo. RESULTS: The simulations for the layered medium model suggest that operating the SonoKnife at frequency of 1 MHz is more effective and safer than 3.5 MHz providing skin cooling is applied prior to ablation. These predictions were in agreement with the results observed in the animal studies. The required sonication time for ablation increased from 50 to 300 s by using 1 MHz. CONCLUSION: Our modelling and animal studies suggest that 1 MHz with pretreatment skin cooling are the optimal settings to operate the SonoKnife to safely and effectively perform subcutaneous thermal ablation of porcine skin. More work is needed to optimise skin cooling and define the optimal sonication time.

Tumour thermotolerance, a physiological phenomenon involving vessel normalisation.

The purpose of this study was to delineate the mechanisms by which stromal components of cancer may induce tumour thermotolerance and exploit alterations in stromal and tumour physiology to enhance radiation therapy. The vascular thermoresponse was monitored by daily one-hour 41.5°C heatings in two murine solid tumour models, SCK murine mammary carcinoma and B16F10 melanoma. A transient increase was seen in overall tumour oxygenation for 2-3 days, followed by a progressive decline in tumour pO(2) upon continued daily heatings. Vascular thermotolerance was further studied by treating tumours with different heating strategies, i.e. (1) a single 60 min 41.5°C treatment; (2) two consecutive daily treatments of 41.5°C for 60 min; (3) a single 60 min 43°C treatment or (4) two days of 41.5°C for 60 min followed by treatment with 43°C for 60 min on the third day. Pre-heating tumours with mild temperature hyperthermia induced vascular thermotolerance, which was accompanied by evidence of vessel normalisation, i.e. a decrease in microvessel density and an increase in pericyte coverage. Rational scheduling of fractionated radiation during heat-induced increases in tumour oxygen levels rendered a significantly greater, synergistic, tumour growth inhibition. In vitro clonogenic survival responses of the individual cell types associated (endothelial cells, fibroblasts, pericytes and tumour cells) indicated only a direct cellular thermotolerance in endothelial cells. Overall, this suggests that tumour thermotolerance is a physiological phenomenon mediated through improvement of functional vasculature.

Prevention and mitigation of acute death of mice after abdominal irradiation by the antioxidant N-acetyl-cysteine (NAC).

Gastrointestinal (GI) injury is a major cause of acute death after total-body exposure to large doses of ionizing radiation, but the cellular and molecular explanations for GI death remain dubious. To address this issue, we developed a murine abdominal irradiation model. Mice were irradiated with a single dose of X rays to the abdomen, treated with daily s.c. injection of N-acetyl-l-cysteine (NAC) or vehicle for 7 days starting either 4 h before or 2 h after irradiation, and monitored for up to 30 days. Separately, mice from each group were assayed 6 days after irradiation for bone marrow reactive oxygen species (ROS), ex vivo colony formation of bone marrow stromal cells, and histological changes in the duodenum. Irradiation of the abdomen caused dose-dependent weight loss and mortality. Radiation-induced acute death was preceded not only by a massive loss of duodenal villi but also, surprisingly, abscopal suppression of stromal cells and elevation of ROS in the nonirradiated bone marrow. NAC diminished these radiation-induced changes and improved 10- and 30-day survival rates to >50% compared with <5% in vehicle-treated controls. Our data establish a central role for abscopal stimulation of bone marrow ROS in acute death in mice after abdominal irradiation.

Dead or alive? Autofluorescence distinguishes heat-fixed from viable cells.

PURPOSE: A proof-of-concept study to evaluate a new autofluorescence method to differentiate necrotic thermally fixed cells from viable tissue following thermal ablation. METHODS: A conductive interstitial thermal therapy (CITT) device was used to ablate swine mammary tissue and rabbit VX-2 carcinomas in vivo. The ablated regions and 10-mm margins were resected 24 h following treatment, embedded in HistOmer and sectioned at 3 mm. The fresh sections were evaluated for gross viability with triphenyl tetrazolium chloride, 1 h post-resection. Representative non-viable and viable areas were then processed and embedded into paraffin, and sectioned at 5 microm. Standard H&E staining and proliferating cell nuclear antigen (PCNA) immunohistochemistry were compared against autofluorescence intensity, at 488-nm wavelength, for cellular viability. RESULTS: Heat-fixed cells in non-viable regions exhibit increased autofluorescence intensity compared to viable tissue (area under receiver operating characteristics (ROC) curve = 0.96; Mann-Whitney P < 0.0001). An autofluorescence intensity-based classification rule achieved 92% sensitivity with 100% specificity for distinguishing non-viable from viable samples. In contrast, PCNA staining did not reliably distinguish heat-fixed, dead cells from viable cells. CONCLUSIONS: Examination of H&E-stained sections using autofluorescence intensity-based classification is a reliable and readily available method to accurately identify heat-fixed cells in ablated surgical margins.

Feasibility of concurrent treatment with the scanning ultrasound reflector linear array system (SURLAS) and the helical tomotherapy system.

PURPOSE: To evaluate the feasibility of concurrent treatment with the scanning ultrasound reflector linear array system (SURLAS) and helical tomotherapy (HT) intensity modulated radiation therapy (IMRT). METHODS: The SURLAS was placed on a RANDO phantom simulating a patient with superficial or deep recurrent breast cancer. A megavoltage CT (MVCT) of the phantom with and without the SURLAS was obtained in the HT system. MVCT images with the SURLAS were obtained for two configurations: (1) with the SURLAS's long axis parallel and (2) perpendicular to the longitudinal axis of the phantom. The MVCT simulation data set was then transferred to a radiation therapy planning station. Organs at risk (OAR) were contoured including the lungs, heart, abdomen and spinal cord. The metallic parts of the SURLAS were contoured as well and constraints were assigned to completely or directionally block radiation through them. The MVCT simulation data set and regions of interest (ROI) files were subsequently transferred to the HT planning station. Several HT plans were obtained with optimization parameters that are usually used in the clinic. For comparison purposes, planning was also performed without the SURLAS on the phantom. RESULTS: All plans with the SURLAS on the phantom showed adequate dose covering 95% of the planning target volume (PTV D95%), average dose and coefficient of variation of the planning target volume (PTV) dose distribution regardless of the SURLAS's orientation with respect to the RANDO phantom. Likewise, all OAR showed clinically acceptable dose values. Spatial dose distributions and dose-volume histogram (DVH) evaluation showed negligible plan degradation due to the presence of the SURLAS. Beam-on time varied depending on the selected optimization parameters. CONCLUSION: From the perspective of the radiation dosage, concurrent treatment with the SURLAS and HT IMRT is feasible as demonstrated by the obtained clinically acceptable treatment plans. In addition, proper orientation of the SURLAS may be of benefit in reducing dose to organs at risk in some cases.

Influence of the SURLAS applicator on radiation dose distributions during simultaneous thermoradiotherapy with helical tomotherapy.

Simultaneous thermoradiotherapy has been shown to maximize the effect of hyperthermia as a radiation sensitizer in cancer treatment. Here we follow our previous work on feasibility of thermoradiotherapy with the scanning ultrasound reflector linear array system (SURLAS) and TomoTherapy HiArt treatment system, and investigate the influence of the SURLAS hyperthermia applicator on delivered radiation dose with the TomoTherapy. A radiation treatment plan was calculated and the treatment was delivered to a phantom with SURLAS on top simulating the likely clinical setup. Proper positioning of the SURLAS was assisted with a magnetic position-and-orientation tracking device (POTD) and was verified with megavoltage-computed tomography. The delivered dose was measured with an ionization chamber (point measurement) and a radiographic film (2D dose distributions). The planned and delivered point dose data agreed within 0.61% +/- 0.63%. Planar dose data agreed within a dose difference of < or =3% of the maximum dose, and a distance-to-dose-agreement of < or =1 mm. The susceptibility of the delivered radiation dose on correct SURLAS positioning was studied as well. The largest dose discrepancy was measured for a position for which a maximum number of radiation beams intersected the incorrectly positioned SURLAS within one TomoTherapy gantry rotation. The point dose disagreed by 6.14% +/- 0.52%, and 2.25% of pixels of the 2D dose distribution did not pass the 3% dose difference/1 mm distance-to-dose-agreement criteria. Our study showed that correct positioning of the SURLAS applicator had an influence on the delivered radiation dose. Delivered and planned dose distributions were in an excellent agreement when SURLAS was positioned according to the treatment plan. Moving the applicator from its planned position was found to cause a modification of delivered dose distributions. A precise and reproducible positioning of the applicator was assured with a POTD.

The heat shock response: role in radiation biology and cancer therapy.

Since prehistoric times, elevated temperatures have been used to treat cancer in a variety of forms. In modern times (the last 40 years) efforts have concentrated on combining heat with other anti-tumour modalities, principally ionizing radiation and some chemotherapeutic drugs. Despite the emphasis on combined therapy, rodent data relating to heat sensitivity and thermal tolerance development assumed principal importance. These considerations suggested treating at 43 degrees C as a target temperature and fractionation schemes emphasizing thermal tolerance avoidance. Concomitantly crucial data on heat-induced tumour reoxygenation and its temperature dependence were largely ignored. In reality these were unrealistic and undesirable goals. The preponderance of evidence now suggests that lower temperatures (40-42 degrees C) administered more frequently, optimally immediately before and during each administration of ionizing radiation, are likely to yield optimal results. Factoring in trimodality therapy and other combinations of chemotherapeutic drugs will require some modifications of such fractionation schemes.