High Intensity Focused Ultrasound Parameters Research Articles

Clinical efficacy and safety of high-intensity focused ultrasound combined with ultrasound-guided suction curettage at different time intervals for Cesarean scar pregnancy: a retrospective study

Objective This study aims to assess the clinical efficacy and safety of combining high-intensity focused ultrasound (HIFU) with ultrasound-guided suction curettage for the treatment of cesarean scar pregnancy (CSP) at different time intervals. Methods A total of 115 CSP patients were enrolled and divided into two groups based on the time between HIFU ablation and suction curettage. Group A (n = 50) underwent suction curettage 24-48 h after HIFU ablation, while Group B (n = 65) had suction curettage within 6 h of HIFU ablation. The study compared and analyzed the clinical characteristics, treatment success rates, and intraoperative hemorrhage during ultrasound-guided suction curettage. Results The demographic characteristics of the two groups were similar, with no statistically significant differences observed in HIFU parameters, treatment success rates, blood loss, the use of Foley catheter balloons, or hospital expenses (p > 0.05). Importantly, suction curettage performed within 6 h after HIFU ablation resulted in shorter hospitalization times compared to suction curettage performed 24-48 h after the ablation (p < 0.05). Conclusions Suction curettage within 6 h after HIFU ablation is an effective, safe, and cost-efficient treatment for patients diagnosed with CSP.

High Intensity Focused Ultrasound (20MHz) and Cryotherapy as Therapeutic Options for Granuloma Annulare and Other Inflammatory Skin Conditions.

In dermatology, inflammatory skin conditions impose a substantial burden worldwide, with existing therapies showing limited efficacy and side effects. This report aims to compare a novel immunological activation induced by hyperthermic 20MHz high intensity focused ultrasound (HIFU) with conventional cryotherapy. The bioeffects from the two methods are initially investigated by numerical models, and subsequently compared to clinical observations after treatment of a patient with the inflammatory disease granuloma annulare (GA). Clinical responses to moderate energy HIFU and cryotherapy were analysed using numerical models. HIFU-induced pressure and heat transfer were calculated, and a three-layer finite element model simulated temperature distribution and necrotic volume in the skin. Model output was compared to 22 lesions treated with HIFU and 10 with cryotherapy in a patient with GA. Cryotherapy produced a necrotic volume of 138.5mm3 at - 92.7°C. HIFU at 0.3-0.6J/exposure and focal depths of 0.8 or 1.3mm generated necrotic volumes up to only 15.99mm3 at temperatures of 68.3-81.2°C. HIFU achieved full or partial resolution in all treated areas, confirming its hyperthermic immunological activation effect, while cryotherapy also resolved lesions but led to scarring and dyspigmentation. Hyperthermic immunological activation of 20MHz HIFU shows promise for treating inflammatory skin conditions as exemplified by GA. Numerical models demonstrate minimal skin necrosis compared to cryotherapy. Suggested optimal HIFU parameters are 1.3mm focal depth, 0.4-0.5J/exposure, 1mm spacing, and 1mm margin. Further studies on GA and other inflammatory diseases are recommended.

High intensity focused ultrasound atomization and erosion in healthy and tendinopathic tendons

Objective. High-intensity focused ultrasound (HIFU) can induce thermal and mechanical mechanisms in a well-defined focal volume of tissues. Histotripsy is a form of mechanical HIFU that can initiate and interact with bubble(s) to cause shock scattering and perhaps atomization within the bubble(s) to fractionate most soft tissues. Ultrasonic atomization, or the ejection of fine droplets from an acoustically-excited liquid exposed to air, has been shown to erode planar soft tissue surfaces, which has led to theories that atomization is a mechanism in histotripsy. However, healthy tendons show resistance to conventional histotripsy; pre-treatment of tendons with heat increases susceptibility to histotripsy fractionation. This study investigates ultrasonic atomization and erosion from planar healthy and tendinopathic tendon surfaces as we evaluate HIFU parameters for histotripsy in tendons. Approach. Forty-six ex vivo bovine tendon-air interfaces were pre-conditioned to surface wetting, heat baths of 20 °C (unaltered), 37 °C (body temperature), and 58 °C (collagen degradation), collagenase soaks for 1, 3, 5, and 24 h (mimicking tendinopathic tendons), and phosphate buffered saline soaks for 24 h. Ejected fragments, histology, and gross analysis determined erosion success. Tissue displacement from the HIFU radiation force was monitored with high-speed photography, and tissue relaxation was pixel-tracked and fit to a Kelvin–Voigt model to evaluate changes in viscoelastic properties. Main results. Results showed that atomization produced holes in 24 h collagenase tendons and surface pitting in 58 °C, 3 h, and 5 h collagenase tendons. Increased mound heights and viscoelastic constants in pre-heated (to 58 °C) and collagenase-soaking (3+ hours) tendinopathic models caused a decrease in elasticity and/or increase in viscosity, increasing susceptibility to erosion by HIFU atomization. Significance. Therefore, tendons with chronic tendinopathies may be more susceptible than healthy tendons to histotripsy fractionation.

Abstract 1700: Immune effects of high intensity focused ultrasound ablation with checkpoint inhibitors in murine neuroblastoma

Abstract Background: Pediatric solid tumors have not shared in the success of immunotherapy, possibly due to mechanisms impeding an effective immune response. High intensity focused ultrasound (HIFU) ablation uses ultrasound energy to non-invasively and precisely destroy targeted tumor tissue and can cause local inflammatory responses. Our group previously showed a significant survival benefit with increased antitumor cytokine and cellular response treating refractory, murine neuroblastoma (N2a) with HIFU boiling histotripsy (BH) and αCTLA-4 + αPD-L1. We sought to reproduce these bioeffects using HIFU ablation with αCTLA-4 + αPD-L1. Methods: N2a tumors were established in the hindlegs of A/J mice and when tumors reached longest diameter of 12-15mm, mice were treated with 1) HIFU ablation alone (n =36), 2) HIFU ablation with αCTLA-4 + αPD-L1 (n = 35) or 3) no treatment (n = 14). Mice were treated with HIFU ablation (1.5MHz transducer, 35W acoustic power, 3 foci x 5 sec) under ultrasound imaging guidance. αCTLA-4 + αPD-L1 were injected on days 1, 4 and 7 after HIFU ablation. Survival endpoints were euthanasia due to poor clinical status or tumor size &amp;gt;20mm. ELISA (serum), and flow cytometry (tumors, draining and contralateral lymph nodes (DLN , CLN), and spleen) were performed at 24, 48 and 72 hour time points after HIFU ablation alone or with αCTLA-4 + αPD-L1. Results: HIFU ablation alone or with αCTLA-4 + αPD-L1 did not provide a significant survival benefit. Following HIFU ablation alone, there was significant downregulation of CD8α+CD11c+ cells in tumor and DLN but no other statistically significant changes in immune cell markers compared to control. After HIFU ablation and αCTLA-4 + αPD-L1, CD8α+Ki67+ increased in tumor and DLN, but higher expression of CD3+CD8+ was not observed. CD4+FoxP3- cells remained unchanged but CD4+FoxP3+ population increased in the tumor, DLN, CLN and spleen. Interestingly, PD-1 expression was upregulated on CD3+ and CD8α+ cells in tumor, DLN, CLN and spleen. IFN-Γ, CXCL-10 and TNF-α were unchanged after HIFU ablation alone but increased following the combination therapy. IL-10 and VEGF-A were not affected by either treatment and KC/GRO decreased steadily after HIFU ablation with αCTLA-4 + αPD-L1. Conclusion: Unlike BH with immunotherapy, HIFU ablation with immunotherapy did not improve survival in this N2a model. HIFU ablation and αCTLA-4 + αPD-L1 did not produce a profound immune response and favored a regulatory T cell response with protumor activity. This is in stark contrast to the immune response seen with BH and immunotherapy despite the same tumor model and experimental set up. It will be important to understand the role of PD-1 and other protumoral factors, to investigate the effect of other HIFU parameters on systemic immune antitumor response and to evaluate this approach in other murine cell line models for broader clinical applicability of this combination therapy. Citation Format: Caitlin Tydings, Avinash Eranki, Karun V. Sharma, AeRang Kim, Priya Srinivasan, Christopher Lazarski, Christopher Rossi. Immune effects of high intensity focused ultrasound ablation with checkpoint inhibitors in murine neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1700.

Magnetic nanoparticles-enhanced focused ultrasound heating: size effect, mechanism, and performance analysis

High intensity focused ultrasound (HIFU) has attracted great interest as a new energy-based technique to treat disordered tissues, such as tumors, through a hyperthermal mechanism using ultrasonic waves. However, long treatment times and collateral damage to healthy tissues due to high acoustic powers are still challenges for the clinical application of HIFU. One possible strategy to enhance the deposition efficiency of HIFU at the tumor site is to employ magnetic nanoparticles (MNPs) as ultrasound absorption agents for the thermal therapy. The objectives of the current study are threefold: (i) to examine the effects of MNP features, including the size and volume concentration, on the thermal mechanism of HIFU (ii) to investigate the performance of MNPs as they were exposed to ultrasound fields at different ranges of power and frequency (iii) and to study the interaction mechanism between MNPs and ultrasonic waves during the MNPs-enhanced HIFU process. To this end, we developed an ultrasound-guided HIFU system to conduct an in vitro experimental study on tissue phantoms containing MNPs of different sizes and volume concentrations. A set of HIFU parameters such as temperature rise and the rate of absorbed energy was monitored to examine the role of MNPs during the NPs-enhanced HIFU thermal procedure. Results showed that the MNPs significantly improved the thermal effect of HIFU by enhancing the rate of energy converted to heat and the temperature rise at the focal region. Moreover, it was demonstrated that the increase of MNP size and volume concentration greatly enhanced the HIFU parameters; the effects of MNPs were further improved by increasing the power and frequency of acoustic field.

Theranostic MRI liposomes for magnetic targeting and ultrasound triggered release of the antivascular CA4P

Theranostic nanocarriers of antivascular drug encapsulated in thermosensitive ultramagnetic liposomes can be advantageously designed to provide a locally high concentration and an active delivery, with image-guided Magnetic Resonance Imaging (MRI) so as to reliably cure tumor. We propose a novel therapeutic strategy consisting of the magnetic accumulation of Ultra Magnetic Liposomes (UML) followed by High-Intensity Focused Ultrasound (HIFU) to trigger the release of an antivascular agent monitored by MRI. For this purpose, we co-encapsulated Combretastatin A4 phosphate (CA4P), a vascular disrupting agent, in the core of UML to obtain CA4P-loaded thermosensitive Ultra Magnetic Liposomes (CA4P-UML). To assess the HIFU parameters, the CA4P release has been triggered in vitro by local heating HIFU at the lipids transition temperature. Morphology of endothelial cells was assessed to evaluate the effect of encapsulated versus non-encapsulated CA4P. The efficiency of a treatment combining the magnetic targeting of CA4P-UML with the CA4P release triggered by HIFU was studied in CT26 murine tumors. Tumor perfusion and volume regression parameters were monitored by multiparametric quantitative anatomical and dynamic in vivo MRI at 7 T. Additionally, vascularization and cellularity were evaluated ex-vivo by histology. This thorough investigation showed that the combined treatment exhibited a full benefit. A 150-fold improvement compared with the chemotherapy alone was obtained using a magnetic targeting of CA4P-UML triggered by HIFU, and was consistent with an expected effect on vascularization 24 h after treatment.

MRI evaluation of endopelvic fascial swelling and analysis of influencing factors in patients with uterine fibroids after high-intensity focused ultrasound ablation

Purpose To evaluate endopelvic fascial swelling in patients with uterine fibroids after high-intensity focused ultrasound (HIFU) ablation on magnetic resonance imaging (MRI) and investigate the factors that influence endopelvic fascial swelling. Methods MRI and clinical data from 188 patients with uterine fibroids who were treated with HIFU were analyzed retrospectively. The patients were divided into a fascial swelling group and a non-swelling group, and the degree of swelling was graded. Fascial swelling was set as the dependent variable, and factors such as baseline characteristics and HIFU parameters, were set as the independent variables. The relationship between these variables and fascial swelling was analyzed by univariate and multivariate analyses. Correlations between the factors and the degree of fascial swelling were evaluated by Kruskal–Wallis test. Results The univariate analysis revealed that the fibroid location, distance from the fibroid to the sacrum, sonication time, treatment time, treatment intensity, therapeutic dose (TD), and energy efficiency (EEF) all affected the endopelvic fascial swelling (p < 0.05). Subsequently, multivariate analysis showed that the distance from the fibroid to the sacrum was significantly correlated with fascial swelling (p < 0.05). Moreover, TD and sonication time were significantly positively correlated with the degree of fascial swelling (p < 0.05). The incidence of sacrococcygeal pain was significantly correlated with fascial swelling (p < 0.05). Conclusion The distance from the fibroid to the sacrum was a protective factor for fascial swelling. TD and sonication time were significantly positively correlated with the degree of fascial swelling.

Effect of hydrodynamic cavitation in the tissue erosion by pulsed high-intensity focused ultrasound (pHIFU)

High-intensity focused ultrasound (HIFU) is emerging as an effective therapeutic modality in clinics. Besides the thermal ablation, tissue disintegration is also possible because of the interaction between the distorted HIFU bursts and either bubble cloud or boiling bubble. Hydrodynamic cavitation is another type of cavitation and has been employed widely in industry, but its role in mechanical erosion to tissue is not clearly known. In this study, the bubble dynamics immediately after the termination of HIFU exposure in the transparent gel phantom was captured by high-speed photography, from which the bubble displacement towards the transducer and the changes of bubble size was quantitatively determined. The characteristics of hydrodynamic cavitation due to the release of the acoustic radiation force and relaxation of compressed surrounding medium were found to associate with the number of pulses delivered and HIFU parameters (i.e. pulse duration and pulse repetition frequency). Because of the initial big bubble (~1 mm), large bubble expansion (up to 1.76 folds), and quick bubble motion (up to ~1 m s−1) hydrodynamic cavitation is significant after HIFU exposure and may lead to mechanical erosion. The shielding effect of residual tiny bubbles would reduce the acoustic energy delivered to the pre-existing bubble at the focus and, subsequently, the hydrodynamic cavitation effect. Tadpole shape of mechanical erosion in ex vivo porcine kidney samples was similar to the contour of bubble dynamics in the gel. Liquefied tissue was observed to emit towards the transducer through the punctured tissue after HIFU exposure in the sonography. In summary, the release of HIFU exposure-induced hydrodynamic cavitation produces significant bubble expansion and motion, which may be another important mechanism of tissue erosion. Understanding its mechanism and optimizing the outcome would broaden and enhance HIFU applications.

Abstract 2145: Elimination of multidrug-resistant glioma cells using unique sequence of high-intensity focused ultrasound and low-dose generic chemotherapeutic

Abstract BACKGROUND Despite medical advances, multidrug-resistant (MDR) gliomas continue to challenge the patients. In this study, I evaluate a new strategy in which the unique sequence of High-Intensity Focused Ultrasound (HIFU) and low-dose generic chemotherapeutic is utilized to attack MDR glioma cells. METHODS This strategy, motivated by recent clinical trials in which HIFU was used to non-invasively disrupt the blood-brain barrier and to treat brain tumors, led to the in vitro study during which human glioma cell line U87 (ATCC), modified for overexpression of epidermal growth factor receptor (EGFR), was paradoxically treated with low-dose Etoposide (VP-16). Day 1: Each data sample consisted of ∼10K cells grown inside a well of 8-well glass slides (Lab-Tek). Each slide was then filled with growth media, sealed, submerged in a 37ºC degassed water bath and secured onto a fixture. The targets for HIFU therapy are the center points of the 4 quadrants of each well's base. The constant HIFU parameters for each slide were acoustic pressure 4.5 MPa, repetition rate 1 Hz, focal-zone depth and 30 sec/sonication/center point while HIFU duty cycle (DC) ranged 0-50% among slides. After HIFU treatment, the slides were incubated for 24h. Day 2: Cell media for each slide was replaced with fresh media containing [VP-16] 0-100 uM prior to repeating the HIFU procedure from day 1. Day 4: After 48h of exposure to VP-16, cell survivability study was performed using cell-count technique to determine the contribution of HIFU-mediated necrosis as well as VP-16-mediated apoptosis. RESULTS Cell survivability decreased by increasing [VP-16] or HIFU DC. In VP-16-only group (HIFU DC 0%), average survivability was 85% (n = 4) at [VP-16] 1 uM. In HIFU-only group ([VP-16] 0 uM), average survivability was 34% (n = 4) at DC 50%. In contrast, average survivability was 12% (n = 4), using [VP-16] 1 uM and DC 50%. CONCLUSION The unique sequence of HIFU and low-dose Etoposide virtually eliminated MDR glioma cells on day 4. in vitro Treatment of Multidrug-Resistant Glioma Cell Line U87 Using HIFU-Etoposide Sequence[Etoposide] = [VP-16], (uM)00.5151050100Average cell survivability (%) ± SD on day 4 (Etoposide only; DC 0%; n = 4)100 ± 47 (control)62 ± 2385 ± 1341 ± 537 ± 725 ± 421 ± 6Average cell survivability (%) ± SD on day 4 (DC 50%; n = 4)34 ± 5 (HIFU only)14 ± 712 ± 66 ± 24 ± 23 ± 14 ± 1Note: The above data suggests that, in principle, drug resistance may be reversible and that the unique sequence of HIFU and a low-dose generic drug may be a promising alternative to current treatments (multidrug regimen, surgery or radiotherapy) against other MDR solid cancers. In addition to high efficacy within a relatively short time, the low cost and the potential absence of drug side effects from using low-dose generic chemotherapeutic are exciting motivations to further investigate this new cancer treatment in animal studies. Citation Format: Howard Q. Vo. Elimination of multidrug-resistant glioma cells using unique sequence of high-intensity focused ultrasound and low-dose generic chemotherapeutic. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2145.

Treatment of multi-drug-resistant hepatoblastoma cells using unique sequence of high-intensity focused ultrasound and low-dose generic chemotherapeutic.

e22008 Background: High-intensity focused ultrasound (HIFU) is a noninvasive, radiation-free, and precisely targeted form of cancer therapy. In this study, I evaluate a new strategy in which the unique sequence of HIFU and low-dose generic chemotherapeutic is utilized to kill multidrug-resistant (MDR) hepatoblastoma cells. Methods: My strategy, motivated by clinical HIFU trials in adult hepatocellular cancers, led to the in vitro study in which human hepatoblastoma cell line HepG2 (ATCC HB8065), known for resistance to 5-fluorouracil (5-FU), was paradoxically treated with low-dose 5-FU in the following sequence. Day 0: Each data sample consisted of ~10K HepG2 cells grown inside a well of 8-well glass slides (Lab-Tek). Each well was then filled with growth media and incubated at 37ºC for 24h. Day 1: Each slide was sealed, submerged in a 37ºC degassed water bath and secured onto a fixture. The targets for HIFU therapy are the center points of the 4 quadrants of each well's base and the common origin. The constant HIFU parameters for each slide were acoustic pressure 4.5 MPa, repetition rate 1 Hz, focal-zone depth and 30 sec/sonication/target while HIFU duty cycle (DC) ranged 0-50% among slides. After HIFU treatment, the slides were incubated for 24h. Day 2: Cell media for each slide was replaced with fresh media containing [5-FU] 0-400 uM prior to repeating HIFU procedure from day 1. Day 4: After 48h of exposure to 5-FU, cell survivability study using imaging-based live cell count was performed to determine the contributions of HIFU-mediated necrosis and 5-FU-mediated apoptosis/necrosis. Results: Cell survivability of MDR HepG2 cells decreased further using HIFU/5-FU sequence than with either HIFU or 5-FU alone as shown below (Table). Conclusions: The unique sequence of HIFU and low-dose 5-fluorouracil was successful in eliminating MDR hepatoblastoma cells on day 4. Treatment of HepG2 hepatoblastoma cells using HIFU/5-FU sequence. [5-FU], (uM) 0 1 10 100 200 400 95% CI of cell survivability (%) on day 4 = estimate ± margin of error;HIFU DC 0%, N=4 100± 12 81± 37 44± 13 30± 4 34± 5 39± 3 95% CI of cell survivability (%) on day 4 = estimate ± margin of error; HIFU DC 50%, N=4 30±5 7±1 10± 4 10± 2 11± 3 8±3

Comparison of the synergistic effect of lipid nanobubbles and SonoVue microbubbles for high intensity focused ultrasound thermal ablation of tumors

Microbubbles (MBs) are considered as an important enhancer for high intensity focused ultrasound (HIFU) treatment of benign or malignant tumors. Recently, different sizes of gas-filled bubbles have been investigated to improve the therapeutic efficiency of HIFU thermal ablation and reduce side effects associated with ultrasound power and irradiation time. However, nanobubbles (NBs) as an ultrasound contrast agent for synergistic therapy of HIFU thermal ablation remain controversial due to their small nano-size in diameter. In this study, phospholipid-shell and gas-core NBs with a narrow size range of 500–600 nm were developed. The synergistic effect of NBs for HIFU thermal ablation was carefully studied both in excised bovine livers and in breast tumor models of rabbits, and made a critical comparison with that of commercial SonoVue microbubbles (SonoVue MBs). In addition, the pathological changes of the targeted area in tumor tissue after HIFU ablation were further investigated. Phosphate buffer saline (PBS) was used as the control. Under the same HIFU parameters, the quantitative echo intensity of B-mode ultrasound image and the volume of coagulative necrosis in lipid NBs groups were significantly higher and larger than that in PBS groups, but could not be demonstrated a difference to that in SonoVue MBs groups both ex vivo and in vivo. These results showed that the synergistic effect of lipid NBs for HIFU thermal ablation were similar with that of SonoVue MBs, and further indicate that lipid NBs could potentially become an enhancer for HIFU thermal ablation of tumors.

Enhancement of Small Molecule Delivery by Pulsed High-Intensity Focused Ultrasound: A Parameter Exploration

Chemotherapeutic drug delivery is often ineffective within solid tumors, but increasing the drug dose would result in systemic toxicity. The use of high-intensity focused ultrasound (HIFU) has the potential to enhance penetration of small molecules. However, operation parameters need to be optimized before the use of chemotherapeutic drugs in vivo and translation to clinical trials. In this study, the effects of pulsed HIFU (pHIFU) parameters (spatial-average pulse-average intensity, duty factor and pulse repetition frequency) on the penetration as well as content of small molecules were evaluated in ex vivo porcine kidneys. Specific HIFU parameters resulted in more than 40 times greater Evans blue content and 3.5 times the penetration depth compared with untreated samples. When selected parameters were applied to porcine kidneys in vivo, a 2.3-fold increase in concentration was obtained after a 2-min exposure to pHIFU. Pulsed HIFU has been found to be an effective modality to enhance both the concentration and penetration depth of small molecules in tissue using the optimized HIFU parameters. Although, performed in normal tissue, this study has the promise of translation into tumor tissue.

Abstract 711: Elimination of multi-drug-resistant breast cancer cells using combination of high-intensity focused ultrasound and low-dose generic chemotherapeutic

Abstract PURPOSE Despite medical advances, multidrug-resistant (MDR) breast cancers continue to challenge the patients. In this study, we seek to evaluate a new strategy in which the combination of High-Intensity Focused Ultrasound (HIFU) and low-dose generic chemotherapeutic is utilized to attack MDR breast cancer cells. METHOD This strategy, motivated by clinical trials in which HIFU was used to treat breast fibroadenoma, led to the in vitro study during which human triple-negative breast cancer stem cell line BT-549 (ATCC), known for resistance to Docetaxel (DTX), was paradoxically treated with low-dose DTX. Day 1: Each data sample consisted of ∼10K cells grown inside a well of 8-well glass slides (Lab-Tek). Each slide was then filled with growth media, sealed, submerged in 37ºC degassed water bath and secured onto a fixture. The targets for HIFU therapy are the center points of the 4 quadrants of each well's base. The constant HIFU parameters for each slide were acoustic pressure 5MPa, repetition rate 1Hz, focal-zone depth and 30 sec/sonication/center point while duty cycle (DC) ranged 0-50% among slides. After HIFU treatment, the slides were incubated for 24h. Day 2: Cell media for each slide was replaced with fresh media containing [DTX] 0-4 nM prior to repeating HIFU procedure from day 1. Day 4: After 48h of exposure to DTX, cell survivability study was performed to determine the contribution of HIFU-mediated necrosis as well as necrosis mediated by low [DTX] (versus apoptosis by very high [DTX]). RESULTS Cell survivability decreased by increasing [DTX] or DC. In DTX-only group (DC 0%), average survivability was 42.8% (n = 7) for [DTX] 1nM while in HIFU-only group ([DTX] 0 nM), average survivability was 25.1% (n = 7) at DC 30%. In contrast, there was virtually no survivability of breast cancer stem cells for the combination of [DTX] 1nM and DC ≥ 30%. CONCLUSION The combination of HIFU and low-dose Docetaxel was successful in virtually eliminating MDR breast cancer cells in 4 days. in vitro Treatment of Triple-Negative Breast Cancer Stem Cells Using HIFU-Docetaxel Combination[Docetaxel], (nM)0 (HIFU only)0.250.5124Average Cell Survivability (%) on day 4; DC 0% (Docetaxel only)100.084.553.042.829.514.9Average Cell Survivability (%) on day 4; DC 30%25.12.22.81.71.53.8Independent t-test p-value (n = 7)0.0034680.0036640.0200840.0017810.0019270.00116Note: Our data suggests that, in principle, drug resistance may be reversible and that a combination of HIFU and a low-dose generic chemotherapeutic may be a promising alternative to existing treatments (multidrug regimen, surgery or radiotherapy) against other MDR cancers. In addition to high efficacy within a relatively short time, the minimal/no side effects and low cost from using low-dose generic chemotherapeutic may pave the way toward a paradigm shift in near-future cancer treatments. Citation Format: Howard Q. Vo, Yoo-Shin Kim, Brian E. O'Neill. Elimination of multi-drug-resistant breast cancer cells using combination of high-intensity focused ultrasound and low-dose generic chemotherapeutic. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 711. doi:10.1158/1538-7445.AM2015-711

Clinical value of 125I seeds implantation combined with high intensity focused ultrasound for the treatment of portal vein tumor thrombus from hepatocellular carcinoma

Objective To investigate the clinical efficacy and feasibility of 125I seeds implantation combined with high intensity focused ultrasound (HIFU) for portal vein tumor thrombus (PVTT) from HCC. Methods Nineteen cases of PVTT from HCC (17 males, 2 females; average age: 50 years, stage: Ⅰ-Ⅲ) undergoing 125I seeds implantation combined with HIFU from March 2011 to October 2013 were retrospectively studied. The radioactivity of each 125I seed was 18.5 MBq and the matched peripheral dose was 90-120 Gy. HIFU parameters were set as follows: ultrasound wave frequency, 0.85 mHz; output power, 300-400 W; total treatment duration, 33-70 min. During the follow-up of 3-24 months, the change of PVTT size, postoperative complications and survival rate were recorded. Kaplan-Meier method was used to analyze the survival rate. Results The treatment was successfully completed in all patients and no serious complications were observed. After 1 month of follow-up, the tumor thrombi shrank in all patients. Among 19 patients, 9 achieved PR, 4 SD, 6 PD. The one-year and two-year survival rates were 47.4% and 7.9%, respectively. The mean survival was 11.6±3.0 months (range: 3-24 months). The median postoperative survival for stagesⅠ, Ⅱ, Ⅲ was 13.5, 7.0, 4.0 months, respectively. Conclusion 125I seeds implantation combined with HIFU could be a safe and effective therapy for PVTT from HCC. Key words: Liver neoplasms; Thrombosis; Portal vein; Brachytherapy; Iodine radioisotopes; Ultrasound, high intensity focused

Potential Femoral Head Osteonecrosis Model Induced by High-Intensity Focused Ultrasound

Osteonecrosis of the femoral head is a common disease that can result in complex hip replacement. To evaluate potential treatments, a model that consistently creates osteonecrosis is needed. We studied and demonstrated the possibility of developing an osteonecrosis model using high-intensity focused ultrasound (HIFU) on canine femora in vitro. To achieve these goals, the temperature in the medullary cavity of the femoral head was measured. A phenomenological model was developed to fit the measured temperature variations with the HIFU parameters for similar HIFU experiments on femoral heads. The average temperature discrepancy between model and measured values was less than 0.83°C. Histology confirmed that the temperature in the medullary cavity can be elevated to a level at which an acute thermal injury is created. HIFU has the potential to be used in a non-invasive model of osteonecrosis.

Generation of uniform lesions in high intensity focused ultrasound ablation

High intensity focused ultrasound (HIFU) is emerging as an effective oncology treatment modality according to the clinical experience in the last decade. The temperature at the focus can reach over 65°C within seconds, denaturing cellular proteins and resulting in coagulative necrosis. HIFU parameters are usually kept the same for each treatment spot in tumor ablation. Because of the thermal diffusion from nearby spots, the lesion size will gradually increase as the HIFU therapy progresses, which leads to insufficient treatment of initial spots and over exposure of later ones. From the viewpoint of the physician, uniform lesions with the least energy exposure and the least energy are preferred in tumor ablation. In this study, an algorithm was developed to determine the number of HIFU pulses delivered to each spot in order to generate uniform lesions that fill the region-of-interest completely. The exposure energies required using different scanning pathways (raster scanning, spiral scanning from the center to the outside, and spiral scanning from the outside to the center), spot spacing (1mm, 2mm, 4mm, and 6mm) and motion time (from 0s to 400s) were compared with each other. It is found that spiral scanning from the outside to the center with spot spacing of 2mm and motion time less than 10s needs the least numbers of pulses or HIFU energy in uniform lesion production with the minimal temperature elevation. In addition, the effects of thermal properties of tissue (i.e., specific heat capacity, convective heat transfer coefficient, and thermal conductivity) on HIFU ablation were investigated in order to determine the HIFU treatment planning for various targets. Uniform lesion production in the transparent gel phantom and ex vivo bovine liver samples using the proposed algorithm proved effective and accord with the simulation for different scanning pathways by an extracorporeal clinical HIFU system. Therefore, dynamically adjusting ultrasound exposure energy can improve the efficacy and safety of HIFU ablation, and the treatment planning depends on the scanning protocol and thermal properties of the target.

The Effect of the Scanning Pathway in High-Intensity Focused Ultrasound Therapy on Lesion Production

Because tumors are much larger in size compared with the beam width of high-intensity focused ultrasound (HIFU), raster scanning throughout the entire target is conventionally performed for HIFU thermal ablation. Thermal diffusion affects the temperature elevation and the consequent lesion formation. As a result, the lesion will grow continuously over the course of HIFU therapy. The purpose of this study was to investigate the influence of scanning pathways on the overall thermal lesion. Two new scanning pathways, spiral scanning from the center to the outside and spiral scanning from the outside to the center, were proposed with the same HIFU parameters (power and exposure time) for each treatment spot. The lesions produced in the gel phantom and bovine liver were compared with those using raster scanning. Although more uniform lesions can be achieved using the new scanning pathways, the produced lesion areas (27.5 ± 12.3 mm 2 and 65.2 ± 9.6 mm 2, respectively) in the gel phantom are significantly smaller ( p < 0.05) than those using raster scanning (92.9 ± 11.8 mm 2). Furthermore, the lesion patterns in the gel phantom and bovine liver were similar to the simulations using temperature and thermal dose-threshold models, respectively. Thermal diffusion, the scanning pathway and the biophysical aspects of the target all play important roles in HIFU lesion production. By selecting the appropriate scanning pathway and varying the parameters as ablation progresses, HIFU therapy can achieve uniform lesions while minimizing the total delivered energy and treatment time.

1473 TREATMENT FOR RECURRENT LOCALIZED PROSTATE CANCER (PCA) FOLLOWING RADIATION FAILURE WITH HIGH INTENSITY FOCUSED ULTRASOUND (HIFU) RESULTS WITH SONABLATE® 500

You have accessJournal of UrologyProstate Cancer: Localized1 Apr 20111473 TREATMENT FOR RECURRENT LOCALIZED PROSTATE CANCER (PCA) FOLLOWING RADIATION FAILURE WITH HIGH INTENSITY FOCUSED ULTRASOUND (HIFU) RESULTS WITH SONABLATE® 500 Ana Maria Autran Gomez, Ali Alzaharani, Jonathan Izawa, and Joseph Chin Ana Maria Autran GomezAna Maria Autran Gomez London, Canada More articles by this author , Ali AlzaharaniAli Alzaharani London, Canada More articles by this author , Jonathan IzawaJonathan Izawa London, Canada More articles by this author , and Joseph ChinJoseph Chin London, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1408AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Local relapse after External Beam Radiation (EBRT)or Brachtherapy (BT) for localized PCa has been reported in 30–40%. Currently salvage therapy options include radical prostatectomy, brachytherapy and focal ablation with cryotherapy or HIFU. HIFU is a minimally invasive acoustic ablation technique that uses intersecting, precision focused ultrasound waves to raise the temperature of the target tissue to 80–90oC in 2–3 seconds, destroying the prostatic tissue. Few series have reported the efficacy as salvage therapy in terms of oncologic outcomes. The objective is to determinate the ability of HIFU as a salvage therapy in patients with recurrence of localized PCa followed EBRT or BT. METHODS From April 2006 to Sept 2009, 62 patients (pts) (median age 68.0±5.3 years) with histologically confirmed recurrent localized PCa after EBRT or BT,clinical stage T1–T2, PSA level ≤10ng/ml, pre Gleason score ≤8, and no distant metastasis, were subjected to salvage HIFU using Sonablate®500. PSA levels and IPSS, IIEF-5 questionnaires were assessed at 45, 90, 180 days and 12 months. Follow-up biopsy was done at 180 days after HIFU. Biochemical failure was defined according to the Phoenix criteria. Mann- Whitney test was used with p<0.05 statistical significance. RESULTS The pre HIFU parameters were: PSA 4.08±2.96 ng/ml, prostate volume 25.59±9.59 cc. IPSS 7.52±4.81, IIEF-5 9.10±8.42; pre-salvage Gleason ≤6 in 25cases, Gleason 7 in 24 and Gleason 8 in 13. 55(89%) pts had EBRT and 7 had BT. 16 (26%) pts had androgen deprivation pre-HIFU, discontinued post-op. Mean follow-up was 16 months. At follow-up 13(21%) pts presented local relapse at 180 days. Progression-free survival (PFS) rate at 3 years was 60%. With univariable analysis, prostate volume (p=0.010), IPSS (p=0.002), and IIEF-5 (p=0.010) showed statistical difference at 12 months compared with the basal values. Median PSA value was 0.77ng/ml, 0.62ng/ml, 0.80 ng/ml and 0.64ng/ml at 45, 90, 180 and 12 months respectively. Rectourethral fistula occurred in 2(3%) pts, moderate stress urinary incontinence in 2(3%), and urinary retention requiring intervention in 3(5%). There was no difference in complications between EBRT and BT pts. CONCLUSIONS Our results using HIFU (Sonablate®500) showed a low rate of complications with acceptable oncologic results at short- term, being comparable to the reported literature. HIFU is a viable salvage treatment treatment option. A prospective FDA-sponsored multicenter controlled trial is underway to confirm its utility. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e590-e591 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ana Maria Autran Gomez London, Canada More articles by this author Ali Alzaharani London, Canada More articles by this author Jonathan Izawa London, Canada More articles by this author Joseph Chin London, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

A Comparison of the Thermal-Dose Equation and the Intensity-Time Product, Itm, for Predicting Tissue Damage Thresholds

Thermal dose is the most generally accepted concept for estimating temperature-related tissue damage thresholds in high-intensity focused ultrasound (HIFU) procedures. However, another approach based on the intensity-time product I t m = D has been used, where D is a tissue-dependent damage threshold, I is the spatial-peak, temporal-average intensity and t is time. In this study, these two approaches were compared analytically by substituting a well-known soft-tissue solution for temperature vs. time into the thermal dose equation. From power law fits of I vs. t, m was found to fall between about 0.3 and 0.8. In terms of the intensity required for cell death for a given exposure time, the standard deviation of the error between the full thermal-dose formulation and the I t m = D prediction based upon the power-law fit was less than 5% for focal beam diameters up to 3 mm. Thus, for the practical range of HIFU parameters examined, the intensity-time product relationship is equivalent to the thermal dose formulation. (E-mail: gerald.harris@fda.hhs.gov)

Dynamic Changes of Integrated Backscatter, Attenuation Coefficient and Bubble Activities During High-Intensity Focused Ultrasound (HIFU) Treatment

This paper simultaneously investigated the transient characteristics of integrated backscatter (IBS), attenuation coefficient and bubble activities as time traces before, during and after HIFU treatment, with different HIFU parameters (acoustic power and duty cycle) in both transparent tissue-mimicking phantoms and freshly excised bovine livers. These dynamic changes of acoustic parameters and bubble activities were correlated with the visualization of lesion development selected from photos, conventional B-mode ultrasound images and differential IBS images over the whole procedure of HIFU treatment. Two-dimensional radiofrequency (RF) data were acquired by a modified diagnostic ultrasound scanner to estimate the changes of mean IBS and attenuation coefficient averaged in the lesion region, and to construct the differential IBS images and B-mode ultrasound images simultaneously. Bubble activities over the whole procedure of HIFU treatment were investigated by the passive cavitation detection (PCD) method and the changes in subharmonic and broadband noise were correlated with the transient characteristics of IBS and attenuation coefficient. When HIFU was switched on, IBS and attenuation coefficient increased with the appearance of bubble clouds in the B-mode and differential IBS image. At the same time, the level of subharmonic and broadband noise rose abruptly. Then, there was an initial decrease in the attenuation coefficient, followed by an increase when at lower HIFU power. As the lesion appeared, IBS and attenuation coefficient both increased rapidly to a value twice that of normal. Then the changes in IBS and attenuation coefficient showed more complex patterns, but still showed a slower trend of increases with lesion development. Violent bubble activities were visible in the gel and were evident as strongly echogenic regions in the differential IBS images and B-mode images simultaneously. This was detected by a dramatic high level of subharmonic and broadband noise at the same time. These bubble activities caused fluctuations in IBS and attenuation coefficient during HIFU treatment. After HIFU, IBS and attenuation coefficient decreased gradually accompanied by the fadeout of bright hyperechoic spot in the B-mode and differential IBS image, but were still higher than normal when they were stable. The increases of IBS and attenuation coefficient were greater when using higher acoustic power or a higher duty cycle of the therapeutic emission. These experiments indicated that the bubble activities had the dominant effects on the transient characteristics of IBS and attenuation. This should be taken into consideration when using the dynamic acoustic-property changes for the potentially real-time monitoring imaging of HIFU treatment. (E-mail: mxwan@mail.xjtu.edu.cn)