Quantitative ultrasound imaging for monitoring in situ high-intensity focused ultrasound exposure.

Quantitative ultrasound (QUS) imaging is hypothesized to map temperature elevations induced in tissue with high spatial and temporal resolution. To test this hypothesis, QUS techniques were examined to monitor high-intensity focused ultrasound (HIFU) exposure of tissue. In situ experiments were conducted on mammary adenocarcinoma tumors grown in rats and lesions were formed using a HIFU system. A thermocouple was inserted into the tumor to provide estimates of temperature at one location. Backscattered time-domain waveforms from the tissue during exposure were recorded using a clinical ultrasonic imaging system. Backscatter coefficients were estimated using a reference phantom technique. Two parameters were estimated from the backscatter coefficient (effective scatterer diameter (ESD) and effective acoustic concentration (EAC). The changes in the average parameters in the regions corresponding to the HIFU focus over time were correlated to the temperature readings from the thermocouple. The changes in the EAC parameter were consistently correlated to temperature during both heating and cooling of the tumors. The changes in the ESD did not have a consistent trend with temperature. The mean ESD and EAC before exposure were 120 ± 16 µm and 32 ± 3 dB/cm3, respectively, and changed to 144 ± 9 µm and 51 ± 7 dB/cm3, respectively, just before the last HIFU pulse was delivered to the tissue. After the tissue cooled down to 37 °C, the mean ESD and EAC were 126 ± 8 µm and 35 ± 4 dB/cm3, respectively. Peak temperature in the range of 50-60 °C was recorded by a thermocouple placed just behind the tumor. These results suggest that QUS techniques have the potential to be used for non-invasive monitoring of HIFU exposure.

Assessment of high-intensity focused ultrasound treatment of rodent mammary tumors using ultrasound backscatter coefficients.

Fischer 344 rats with subcutaneous mammary adenocarcinoma tumors were exposed to therapeutic ultrasound at one of three exposure levels (335, 360, and 502 W/cm(2) spatial-peak temporal-average intensity). Quantitative ultrasound estimates were generated from ultrasound radio frequency (RF) data from tumors before and after high-intensity focused ultrasound treatment. Treatment outcome was independently assessed by triphenyl tetrazolium chloride (TTC) staining, histological analysis by a pathologist, and thermocouple data. The average backscatter coefficient (BSC) and integrated backscatter coefficient (IBSC) were estimated before and after therapeutic ultrasound exposure for each tumor from RF data collected using clinical (Ultrasonix Sonix RP) and small-animal (Visualsonics Vevo 2100) array systems. Changes in the BSC with treatment were comparable to inter-sample variation of untreated tumors, but statistically significant differences in the change in the IBSCs were observed when comparing the exposures collectively (p < 0.10 for Sonix RP, p < 0.05 for Vevo 2100). Several exposure levels produced statistically significant differences in the change in IBSC when examined pair-wise, including two exposures having similar intensities (p < 0.05, Vevo 2100). A comparison of the IBSC results with temperature data, histology, and TTC staining revealed that the BSC was not always sensitive to thermal insult and that peak exposure pressure appeared to correlate with observed BSC increases.

Real-Time Volumetric Thermoacoustic Imaging and Thermometry Using a 1.5-D Ultrasound Array.

Noninvasive thermal therapies for the treatment of breast cancer depend on accurate monitoring of tissue temperature to optimize treatment and ensure safety. This work describes a real-time system for 3-D thermoacoustic imaging and thermometry (TAI-TAT) for tracking temperature in tissue samples during heating. The study combines a 2.7-GHz microwave pulse generator with a custom 1.5-D 0.6 MHz ultrasound array for generating and detecting TA signals. The system is tested and validated on slabs of biological tissue and saline gel during heating. Calibration curves for relating the TA signal to temperature were calculated in saline gel (3.40%/°C), muscle (1.73%/°C), and fat (1.15%/°C), respectively. The calibrations were used to produce real-time, volumetric temperature maps at ~3-s intervals with a spatial resolution of approximately 3 mm. TAT temperature changes within a region of interest were compared to adjacent thermocouples with a mean error of 17.3%, 13.2%, and 20.4% for muscle, gel, and fat, respectively. The TAT algorithm was also able to simultaneously track temperatures in different tissues. With further development, noninvasive TAI-TAT may prove to be a valuable method for accurate and real-time feedback during breast cancer ablation therapy.

Effect of Overpressure on Acoustic Emissions and Treated Tissue Histology in ex Vivo Bulk Ultrasound Ablation.

Bulk ultrasound ablation is a thermal therapy approach in which tissue is heated by unfocused or weakly focused sonication (average intensities on the order of 100 W/cm2) to achieve coagulative necrosis within a few minutes exposure time. Assessing the role of bubble activity, including acoustic cavitation and tissue vaporization, in bulk ultrasound ablation may help in making bulk ultrasound ablation safer and more effective for clinical applications. Here, two series of ex vivo ablation trials were conducted to investigate the role of bubble activity and tissue vaporization in bulk ultrasound ablation. Fresh bovine liver tissue was ablated with unfocused, continuous-wave ultrasound using ultrasound image-ablate arrays sonicating at 31 W/cm2 (0.9 MPa amplitude) for either 20 min at a frequency of 3.1 MHz or 10 min at 4.8 MHz. Tissue specimens were maintained at a static overpressure of either 0.52 or 1.2 MPa to suppress bubble activity and tissue vaporization or at atmospheric pressure for control groups. A passive cavitation detector was used to record subharmonic (1.55 or 2.4 MHz), broadband (1.2-1.5 MHz) and low-frequency (5-20 kHz) acoustic emissions. Treated tissue was stained with 2% triphenyl tetrazolium chloride to evaluate thermal lesion dimensions. Subharmonic emissions were significantly reduced in overpressure groups compared with control groups. Correlations observed between acoustic emissions and lesion dimensions were significant and positive for the 3.1-MHz series, but significant and negative for the 4.8-MHz series. The results indicate that for bulk ultrasound ablation, where both acoustic cavitation and tissue vaporization are possible, bubble activity can enhance ablation in the absence of tissue vaporization, but can reduce thermal lesion dimensions in the presence of vaporization.

Frontiers of cancer imaging and guided therapy using ultrasound, light, and microwaves.

This review describes emerging techniques within the last 5 years that employ ultrasound for detecting and staging malignancy, tracking metastasis, and guiding treatment. Ultrasound elastography quantifies soft tissue elastic properties that change as a tumor grows and proliferates. Hybrid imaging modalities that combine ultrasound with light or microwave energy provide novel contrast for mapping blood oxygen saturation, transport of particles through lymphatic vessels and nodes, and real-time feedback for guiding needle biopsies. Combining these methods with smart nanoparticles and contrast agents further promotes new paradigms for cancer imaging and therapy.

Quantitative Ultrasound for Monitoring High-Intensity Focused Ultrasound Treatment In Vivo.

The success of any minimally invasive treatment procedure can be enhanced significantly if combined with a robust noninvasive imaging modality that can monitor therapy in real time. Quantitative ultrasound (QUS) imaging has been widely investigated for monitoring various treatment responses such as chemotherapy, radiation, and thermal therapy. Previously, we demonstrated the feasibility of using spectral-based QUS parameters to monitor high-intensity focused ultrasound (HIFU) treatment of in situ tumors in euthanized rats [Ultrasonic Imaging 36(4), 239-255, 2014]. In the present study, we examined the use of spectral-based QUS parameters to monitor HIFU treatment of in vivo rat mammary adenocarcinoma tumors (MAT) where significant tissue motion was present. HIFU was applied to tumors in rats using a single-element transducer. During the off part of the HIFU duty cycle, ultrasound backscatter was recorded from the tumors using a linear array co-aligned with the HIFU focus. A total of 10 rats were treated with HIFU in this study with an additional sham-treated rat. Spectral parameters from the backscatter coefficient, i.e., effective scatterer diameter (ESD) and effective acoustic concentration (EAC), were estimated. The changes of each parameter during treatment were compared with a temperature profile recorded by a fine-needle thermocouple inserted into the tumor a few millimeters behind the focus of the HIFU transducer. The mean ESD changed from 121 ±6 to [Formula: see text], and the EAC changed from 33 ±2 to [Formula: see text] during HIFU exposure as the temperature increased on average from 38.7 ±1.0 (°)C to 64.2 ±2.7 (°)C. The changes in ESD and EAC were linearly correlated with the changes in tissue temperature during the treatment. When HIFU was turned off, the ESD increased from 81 ±8 to [Formula: see text] and the EAC dropped from 46 ±3 to 36±2 dB/cm(3) as the temperature decreased from 64.2 ±2.7 (°)C to 45 ±2.7 (°)C. QUS was demonstrated in vivo to track temperature elevations caused by HIFU exposure.

In vivo thermal ablation monitoring using ultrasound echo decorrelation imaging.

Previous work indicated that ultrasound echo decorrelation imaging can track and quantify changes in echo signals to predict thermal damage during in vitro radiofrequency ablation (RFA). In the in vivo studies reported here, the feasibility of using echo decorrelation imaging as a treatment monitoring tool was assessed. RFA was performed on normal swine liver (N = 5), and ultrasound ablation using image-ablate arrays was performed on rabbit liver implanted with VX2 tumors (N = 2). Echo decorrelation and integrated backscatter were computed from Hilbert transformed pulse-echo data acquired during RFA and ultrasound ablation treatments. Receiver operating characteristic (ROC) curves were employed to assess the ability of echo decorrelation imaging and integrated backscatter to predict ablation. Area under the ROC curves (AUROC) was determined for RFA and ultrasound ablation using echo decorrelation imaging. Ablation was predicted more accurately using echo decorrelation imaging (AUROC = 0.832 and 0.776 for RFA and ultrasound ablation, respectively) than using integrated backscatter (AUROC = 0.734 and 0.494).

Amplitude modulated chirp excitation to reduce grating lobes and maintain ultrasound intensity at the focus of an array.

During application of high intensity focused ultrasound (HIFU) with therapy arrays, the existence of grating lobes can cause heating at unintended tissue regions. Therefore, the reduction of grating lobes in therapeutic arrays is an important goal. One way to reduce the grating lobes in therapy arrays is to excite the arrays with broadband signals (defined here as >10% fractional bandwidth). To achieve a reduction in grating lobe levels in an ultrasonic array, coded waveforms can be utilized that reduce the grating lobe levels while maintaining the spatial peak temporal average intensity. In this study, a 5-MHz, 9-element, 1.25 mm inter-elemental spacing linear array was excited by a sinusoidal waveform, a conventional linear chirp, and a modified linear chirp. Both chirps spanned the -3-dB bandwidth of the transducer. The conventional chirp was a broadband signal with a linear sweep of frequencies between 2.5 and 7.5 MHz, with all frequency components excited with equal amplitude. The modified chirp signal also swept the frequencies between 2.5 and 7.5 MHz, but the amplitude was weighted such that the edges (low and high frequencies of the band) were excited with more energy than the center of the band. In simulations, the field patterns for the sinusoidal, conventional chirp and modified chirp excitations were produced from the array using Field II and compared. For experiments, the beam pattern from a 5-MHz single-element transducer was mapped using a hydrophone for the sinusoidal, conventional chirp and modified chirp excitation. Each field from the transducer was repeated and summed to produce a field from an array of 9 elements. The difference in the time averaged intensity (in dB) in the main lobe and grating lobes were estimated for each excitation and compared. The results demonstrated that the chirp signals resulted in decreases in grating lobe levels compared to the main lobe, i.e. 10 dB down for focusing and 6 dB down for focusing and steering. A further 1 dB decrease in grating lobe levels was observed for the modified chirp excitation compared to the conventional chirp excitation, which corresponds to ~21% reduction in energy deposition at the grating lobe location.

Treatment of rabbit liver cancer in vivo using miniaturized image-ablate ultrasound arrays.

In the preclinical studies reported here, VX2 cancer within rabbit liver has been treated by bulk ultrasound ablation employing miniaturized image-ablate arrays. Array probes were constructed with 32 elements in a 2.3 × 20 mm(2) aperture, packaged within a 3.1 mm stainless steel tube with a cooling and coupling balloon for in vivo use. The probes were measured capable of 50% fractional bandwidth for pulse-echo imaging (center frequency 4.4 MHz) with >110 W/cm(2) surface intensity available at sonication frequencies 3.5 and 4.8 MHz. B-scan imaging performance of the arrays was measured to be comparable to larger diagnostic linear arrays, although nearfield image quality was reduced by ringdown artifacts. A series of in vivo ablation procedures was performed using an unfocused 32-element aperture firing at 4.8 MHz with exposure durations 20-70.5 s and in situ spatial average, temporal average intensities 22.4-38.5 W/cm(2). Ablation of a complete tumor cross-section was confirmed by vital staining in seven of 12 exposures, with four exposures ablating an additional margin >1 mm beyond the tumor in all directions. Analysis suggests a threshold ablation effect, with complete ablation of tumor cross-sections for exposures with delivery of >838 J acoustic energy. The results show feasibility for in vivo liver cancer ablation using miniaturized image-ablate arrays suitable for interstitial deployment.