High-intensity Focused Ultrasound Ablation Research Articles

Preliminary study on ultrasound-guided high-intensity focused ultrasound ablation for treatment of broad ligament uterine fibroids

Objective To investigate the feasibility, efficacy and safety of ultrasound-guided high-intensity focused ultrasound (HIFU) ablation for treating the broad ligament uterine fibroid (BLUF). Methods A total of 236 patients with symptomatic uterine fibroids were enrolled and treated with JC-200 extracorporeal ultrasound-guided HIFU under conscious sedation between January 2017 and December 2018. Of them, data of 12 patients with 13 broad ligament fibroids were retrospectively analyzed. The patients’ mean age was 38.6 ± 6.3 years. The focused ultrasound target was deployed and moved from the deeper layer to the superficial layer of BLUFs. All patients underwent contrast-enhanced MRI (CE-MRI) before, immediate post-operation, and six months after the HIFU ablation procedure. The fibroid size, non-perfusion volume (NPV) ratio, the reduction of fibroid volumes, adverse events, symptom changes, and abnormal MRI findings associated with the HIFU treatment were analyzed. Results Ultrasound-guided HIFU ablation in the twelve patients was technically successful with one session treatment. The mean longest diameter of BLUFs was 6.2 ± 2.3 cm. The mean NPV ratio of fibroids was 84.08%± 9.4%. After HIFU ablation, lower abdominal pain occurred in 7 cases, sacrococcygeal pain in 3 cases, and mild skin pain in 6 cases. There were no severe adverse events and complications associated with the treatment. At 6 months post-treatment follow-up, the mean fibroid volume decreased by 56.2%± 9.0% (p < 0.05), and the symptoms related to broad ligament fibroids were improved or disappeared Conclusions Ultrasound-guided high-intensity focused ultrasound ablation is feasible, effective, and safe for treating broad ligament fibroids.

High-intensity focused ultrasound (HIFU) ablation versus surgical interventions for the treatment of symptomatic uterine fibroids: a meta-analysis.

To compare the treatment success and safety of ultrasound- and MR-guided high-intensity focused ultrasound (HIFU) with surgery for treating symptomatic uterine fibroids. We searched studies comparing HIFU with surgery for fibroids in different databases from January 2000 to July 2020. The mean difference (MD) or relative risk (RR) with 95% confidence interval (CI) for different outcome parameters was synthesized. We included 10 studies involving 4450 women. Compared with the surgery group, the decrease in uterine fibroid severity score at 6- and 12-month follow-up was higher in the HIFU group (MD - 4.16, 95% CI - 7.39 to - 0.94, and MD - 2.44, 95% CI - 3.67 to - 1.20, p < 0.05). The increase in quality-of-life (QoL) score at 6- and 12-month follow-up was higher in the HIFU group (MD 2.13, 95% CI 0.86 to 3.14, and MD 2.34, 95% CI 0.82 to 3.85, p < 0.05). The duration of hospital stay and the time to return to work was shorter in the HIFU group (MD - 3.41 days, 95% CI - 5.11 to - 1.70, and MD - 11.61 days, 95% CI - 19.73 to - 3.50, p < 0.05). The incidence of significant complications was lower in the HIFU group (RR 0.33, 95% CI 0.13 to 0.81, p < 0.05). The differences in the outcomes of adverse events, symptom recurrence, re-intervention, and pregnancy were not statistically significant (p > 0.05). HIFU is superior to surgery in terms of symptomatic relief, improvement in QoL, recovery, and significant complications. However, HIFU showed comparable effects to surgery regarding the incidence of adverse events, symptom recurrence, re-intervention, and pregnancy. • HIFU ablation is superior to surgery in terms of symptomatic relief, improvement in QoL, recovery, and significant complications. • HIFU has comparable effects to surgery in terms of symptom recurrence rate, re-intervention rate, and pregnancy rate, indicating that HIFU is a promising non-invasive therapy that seems not to raise the risk of recurrence and re-intervention or deteriorate fertility compared to surgical approaches in women with fibroids. • There is still a lack of good-quality comparative data and further randomized studies are necessary to provide sufficient and reliable data, especially on re-intervention rate and pregnancy outcome.

Perfluorooctyl bromide nanoemulsions holding MnO2 nanoparticles with dual-modality imaging and glutathione depletion enhanced HIFU-eliciting tumor immunogenic cell death

Tumor-targeted immunotherapy is a remarkable breakthrough, offering the inimitable advantage of specific tumoricidal effects with reduced immune-associated cytotoxicity. However, existing platforms suffer from low efficacy, inability to induce strong immunogenic cell death (ICD), and restrained capacity of transforming immune-deserted tumors into immune-cultivated ones. Here, an innovative platform, perfluorooctyl bromide (PFOB) nanoemulsions holding MnO2 nanoparticles (MBP), was developed to orchestrate cancer immunotherapy, serving as a theranostic nanoagent for MRI/CT dual-modality imaging and advanced ICD. By simultaneously depleting the GSH and eliciting the ICD effect via high-intensity focused ultrasound (HIFU) therapy, the MBP nanomedicine can regulate the tumor immune microenvironment by inducing maturation of dendritic cells (DCs) and facilitating the activation of CD8+ and CD4+ T cells. The synergistic GSH depletion and HIFU ablation also amplify the inhibition of tumor growth and lung metastasis. Together, these findings inaugurate a new strategy of tumor-targeted immunotherapy, realizing a novel therapeutics paradigm with great clinical significance.

Polyethylenimine (PEI)-modified poly (lactic-co-glycolic) acid (PLGA) nanoparticles conjugated with tumor-homing bacteria facilitate high intensity focused ultrasound-mediated tumor ablation

The acoustic propagation characteristic of ultrasound determines that the energy of ultrasound beam will decrease with the increase of its propagation depth in the body. Similarly, the energy of High Intensity Focused Ultrasound (HIFU) will be attenuated with the increase of HIFU propagation depth in the body. Ensuring sufficient ultrasound energy deposition in the HIFU ablation region for tumor ablation is usually achieved by increasing the ultrasound irradiation power or prolonging the ultrasound ablation time. However, these two methods may damage the normal tissue adjacent to the HIFU ablation region. Herein, we constructed the nanoparticles conjugated with tumor-homing bacteria as the biological tumor-homing synergist to facilitate HIFU-mediated tumor ablation avoiding the potential safety risk. In our strategy, Bifidobacterium bifidum (B.bifidum) was selectively colonized in the hypoxic region of solid tumors after been injected into 4T1 breast cancer bearing-BALB/c mice via the tail vein due to its anaerobic growth characteristic. The amount of B. bifidum with negative surface potential in the hypoxic region of solid tumors was increased by its anaerobic proliferation. Polyethylenimine (PEI) -modified Poly (lactic-co-glycolic) acid nanoparticles loaded sodium bicarbonate (PEI-PLGA-NaHCO3-NPs) with positive surface potential injected into 4T1 breast cancer bearing-BALB/c mice via the tail vein displayed the tumor-homing ability by the electrostatic adsorption with B. bifidum colonized solid tumors. PEI-PLGA-NaHCO3-NPs could release NaHCO3 to produce carbon dioxide (CO2) as cavitation nuclei inside the acidic microenvironment of solid tumors. When HIFU irradiated solid tumors contained with more cavitation nuclei, the ultrasound energy deposition at the tumor region was increased to destroy the tumors more effectively. Meanwhile, the improved efficiency of HIFU-mediated tumor ablation reduced the dependence of the tumor ablation on the ultrasound energy dose, which improved the safety of HIFU-mediated tumor ablation to the non-targeted ablation tissue. This tumor-homing synergist shows the potential application value on the HIFU-mediated tumor ablation in the clinical.

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.

Bifidobacterium bifidum-Mediated Specific Delivery of Nanoparticles for Tumor Therapy

PurposeHypoxia is considered to be obstructive to tumor treatment, but the reduced oxygen surroundings provide a suitable habitat for Bifidobacterium bifidum (BF) to colonize. The anaerobe BF selectively colonizes into tumors following systemic injection due to its preference for the hypoxia in the tumor cores. Therefore, BF may be a potential targeting agent which could be used effectively in tumor treatment. We aimed to determine whether a novel BF-mediated strategy, that was designed to deliver AP-PFH/PLGA NPs (aptamers CCFM641-5-functionalized Perfluorohexane (PFH) loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles) by aptamer-directed approach into solid tumor based on the tumor-targeting ability of BF, could improve efficiency of high intensity focused ultrasound (HIFU) treatment of breast cancer.MethodsWe synthesized AP-PFH/PLGA NPs using double emulsion method and carbodiimide method. Then, we evaluated targeting ability of AP-PFH/PLGA NPs to BF in vivo. Finally, we studied the efficacy of HIFU ablation based on BF plus AP-PFH/PLGA NPs (BF-mediated HIFU ablation) in tumor.ResultsThe elaborately designed AP-PFH/PLGA NPs can target BF colonized in tumor to achieve high tumor accumulation, which can significantly enhance HIFU therapeutic efficiency. We also found that, compared with traditional chemotherapy, this therapy not only inhibits tumor growth, but also significantly prolongs the survival time of mice. More importantly, this treatment strategy has no obvious side effects.ConclusionWe successfully established a novel therapy method, BF-mediated HIFU ablation, which provides an excellent platform for highly efficient and non-invasive therapy of tumor.

An experiment of using the SonoVue ultrasound contrast agent for focused high-intensity ultrasound ablation of uterine fibroids

BACKGROUND: One of the modern methods of organ-saving non-invasive remote treatment of uterine fibroids is ablation of myomatous nodes with high-intensity focused ultrasound (HIFU).&#x0D; AIM: The aim of this study was to analyze changes in the parameters of ultrasonic ablation when using intraoperative control with the help of an ultrasound contrast agent.&#x0D; MATERIALS AND METHODS: In the period from 2016 to 2018, a total of 208 patients with symptomatic uterine myoma underwent HIFU ablation of myomatous nodes. The two groups of patients were compared: group I included 98 patients aged 36 to 52 years (mean age: 44.39 7.12 years) with intraoperative control with an ultrasound contrast agent (sulfur hexafluoride); group II consisted of 110 patients aged 20 to 55 years (mean age: 38.33 8.72 years), whose treatment was not controlled by the contrast agent.&#x0D; RESULTS: Using the Mann-Whitney test, we obtained statistically significant differences in the following parameters: the duration of ultrasound ablation was 215.28 70.57 min (from 70 to 390 min) in group I, and 610.84 56.26 min (from 290 to 1230 min) in group II (p 0.005); the average energy was 329.06 33.06 W in group I, and 293.68 64.51 W in group II (p 0.001); good tolerance of the operation was shown in 91% of cases in group I, and in 61.8% of cases in group II; satisfactory tolerance of the operation was shown in 7.7% of cases in group I, and in 37.3% of cases in group II (p 0.001).&#x0D; CONCLUSIONS: The data obtained indicate that the performance of HIFU ablation with the use of an ultrasonic contrast agent allowed halving the insonation time, while using submaximal and maximum ultrasound exposure powers with better tolerance of intervention by patients.

Focused ultrasound tumour ablation in small animal oncology

The cancer incidence rates for humans and animals remain high, and efforts to improve cancer treatment are crucial. Cancer treatment for solid tumours includes both treatment of the primary tumour and of metastasis. Surgery is commonly employed to resect primary and metastatic tumours, but is invasive, and is not always the optimal treatment modality. Prevention and treatment of metastatic disease often utilizes a multimodal approach, but metastasis remains a major cause of death for both human and veterinary cancer patients. Focused ultrasound (FUS) tumour ablation techniques represent a novel non-invasive approach to treating cancer. FUS ablation is precise, thus sparing adjacent critical structures while ablating the tumour. FUS ablation can occur in a thermal or non-thermal fashion. Thermal FUS ablation, also known as high intensity focused ultrasound (HIFU) ablation, destroys tumour cells via heat, whereas non-thermal FUS, known as histotripsy, ablates tumour cells via mechanical disintegration of tissue. Not only can HIFU and histotripsy ablate tumours, they also demonstrate potential to upregulate the host immune system towards an anti-tumour response. The aim of this report is provide a description of HIFU and histotripsy tumour ablation, with a focus on the basic principles of their ablation mechanisms and their clinical applicability in the field of veterinary oncology.

Carbon nanotube-mediated high intensity focused ultrasound

High intensity focused ultrasound (HIFU) is emerging as a novel therapeutic technique for cancer treatment through a hyperthermal mechanism using ultrasound. However, collateral thermal damages to healthy tissue and skin burns due to the use of high levels of ultrasonic energy during HIFU treatment remain major challenges to clinical application. The main objective of the current study is to evaluate the potential of carbon nanotubes (CNTs) as effective absorption-enhancing agents for HIFU to mediate the heating process at low ultrasonic power levels, and consequently upgrade hyperthermal therapeutic effects of HIFU. An experimental study using in vitro tissue phantoms was conducted to assess the effects of CNTs on HIFU’s heating mechanism. Detailed information was extracted from the experiments for thermal analysis, including rate of absorbed energy density and temperature rise profile at the focal region. Parametric studies were carried out, revealing the effects of ultrasound parameters (ultrasonic power and driving frequency) on the performance of CNTs in various concentrations. The results indicated that CNTs significantly enhanced the thermal effect of HIFU by elevating energy absorption rate and consequential temperature rise. Moreover, it was demonstrated that an increase in ultrasonic power and driving frequency could lead to a better performance of CNTs during HIFU ablation procedures; the effects of CNTs could be further enhanced by increasing their volume concentration inside the medium.

Escherichia coli expressing gas vesicles is safe for enhancing the ablation effect of highintensity focused ultrasound in tumor-bearing mice

To investigate the effect and safety of Escherichia coli (E.coli) expressing gas vesicle (GVs) for enhancing the efficacy of tumor ablation by high intensity focused ultrasound (HIFU) in tumor-bearing mice. Thirty-two female BALB/c mice were used to establish mouse models bearing 4T1 tumor, which were randomized into GVs group [E.coli BL21 (AI)-PET28a-Arg1] and control group (PBS), and the efficacy of HIFU ablation was evaluated by examining coagulative necrotic volume and pathology of the tumors. Another 104 BALB/c mice were also randomly divided into GVs group and control group, and body weight changes of the mice were recorded on days 1, 4 and 15 after intravenous injection of E.coli containing GVs or PBS. White blood cells, red blood cells, hemoglobin and platelet counts and liver and renal function parameters of the mice were detected, and serum levels of TNF-α and IL-1β were examined using ELISA. The pathological changes in the liver and spleen were evaluated using HE staining to assess the safety of the treatments. HIFU ablation resulted in a significantly greater volume of coagulative necrosis and severer tissue damage in GVs group than in the control group (P < 0.001). In the 104 BALB/c mice without tumor cell inoculation, intravenous injection of E.coli expressing GVs, as compared with PBS, did not significantly affect body weight or cause changes in white blood cell, red blood cell and platelet counts or hemoglobin level (P1=0.59, P2=0.27, P3=0.76, P4=0.81). The liver and kidney function parameters (P1=0.12, P2=0.46, P3=0.62, P4=0.86) and serum levels of TNF-α and IL-1β (P1=0.48, P2=0.56) were all comparable between GVs group and control group. No obvious pathological changes were detected in the liver and spleen tissues in either GVs group or the control group. E.coli expressing GVs is safe for enhancing the ablation effect of HIFU in tumor-bearing mice.

Development of a noninvasive HIFU treatment for breast adenocarcinomas using a toroidal transducer based on preliminary attenuation measurements

Breast cancer is the most commonly diagnosed type of cancer among women. For the last fifteen years, treatments that are less invasive than lumpectomy, such as high-intensity focused ultrasound (HIFU) therapy, have been developed, with encouraging results. In this study, a toroidal HIFU transducer was used to create lesions of at least 2 cm in diameter within less than one minute of treatment. The toroidal HIFU transducer created two focal zones that led to large, fast and homogeneous ablations (10.5 cc/min). The experiments were conducted in 30 human samples of normal breast tissues recovered from mastectomies to measure acoustic attenuation (N = 30), and then, HIFU lesions were created (N = 15). Eight HIFU ablations were performed to evaluate the reproducibility of the lesions. HIFU lesions were created in 45 s with a toroidal HIFU transducer working at 2.5 MHz. The longest and shortest axes of the HIFU lesions were 21.7 ± 3.1 mm and 23.5 ± 3.3 mm respectively, corresponding to an average volume of 7.3 ± 1.4 cm3. These HIFU lesions were performed at an average depth of 19.0 ± 1.5 mm, while the integrity of the skin was preserved. The HIFU-treated breast tissues had a higher level of attenuation (0.57 ± 0.11 Np.cm−1.MHz−1) when compared to the untreated tissues (0.21 ± 0.04 Np.cm−1.MHz−1). This study shows the feasibility of a fast and fully noninvasive treatment using a toroidal transducer for breast tumors measuring up to 15 mm in diameter.

The safety of echo contrast-enhanced ultrasound in high-intensity focused ultrasound ablation for abdominal wall endometriosis: a retrospective study.

We aimed to investigate the efficacy and safety of echo contrast-enhanced ultrasound (CEUS) during high-intensity focused ultrasound (HIFU) ablation therapy for abdominal wall endometriosis (AWE). A total of 67 patients with AWE were treated with HIFU ablation, and their demographic characteristics were retrospectively analysed. Blood perfusion of the focal lesion was assessed before the operation, during ablation and after the operation with the use of an ultrasound contrast agent, and the effect of the ultrasound contrast agent on treatment was assessed over a 1-year follow-up period. The degree of symptom relief and adverse effects were evaluated after HIFU ablation. Eighty-two lesions were ablated in 67 patients. CEUS showed that all lesions were successfully ablated with HIFU. The shrinkage ratio of the lesions significantly increased over the follow-up period. Intermittent pain disappeared at 1 month after the operation, and the patients' pain scores significantly decreased at the 1-year follow-up. The mean [± standard deviation (SD)] lesion volume was 7.64±8.95 cm3 on B-mode ultrasound. The post-HIFU non-perfused volume was 18.34±24.08 cm3, and the rate of massive changes on greyscale imaging was 96.16%±5.44% at 12 months. During the procedure, the main complications were a prickling sensation and tenderness in the treatment area and/or a transient "hot" sensation on the skin. After the procedure, there was no obvious discomfort except for pain. Two patients developed an approximately 1-cm area of skin that exhibited a waxy appearance. Seven patients had haematuria. No severe complications were observed. Ultrasound contrast agents are effective and safe for evaluating the effect of HIFU ablation on AWE, and this approach provides significant guidance and evaluation benefits for the use of HIFU treatment for AWE without obvious side effects.

Influence of High-Intensity Focused Ultrasound (HIFU) Ablation on Arteries: Ex Vivo Studies.

High-intensity focused ultrasound (HIFU) has been used to ablate solid tumors and cancers. Because of the hypervascular structure of the tumor and circulating blood inside it, the interaction between the HIFU burst and vessel is a critical issue in the clinical environment. Influences on lesion production and the potential of vessel rupture were investigated in this study for the efficiency and safety of clinical ablation. An extracted porcine artery was embedded in a transparent polyacrylamide gel phantom, with bovine serum albumin (BSA) as an indicator of the thermal lesion, and degassed water was driven through the artery sample. The HIFU focus was aligned to the anterior wall, middle of the artery, and posterior wall. After HIFU ablation, the produced lesion was photographically recorded, and then its size was quantified and compared with that in the gel phantom without artery. In addition, the bubble dynamics (i.e., generation, expansion, motion, and shrinkage of bubbles and their interaction with the artery) were captured using high-speed imaging. It was found that the presence of the artery resulted in a decrease in lesion size in both the axial and lateral directions. The characteristics of the lesion are dependent on the focus alignment. Acoustic and hydrodynamic cavitation play important roles in lesion production and interaction with the artery. Both thermal and mechanical effects were found on the surface of the artery wall after HIFU ablation. However, no vessel rupture was found in this ex vivo study.

Evaluation of Ultrasonic Attenuation in Primary and Secondary Human Liver Tumors and Its Potential Effect on High-Intensity Focused Ultrasound Treatment

Primary and secondary liver tumors are completely different diseases but are usually treated similarly using high-intensity focused ultrasound (HIFU). However, the acoustic parameters of these tissues are not well documented. In this study, attenuation coefficients were evaluated in fresh primary (N = 8) and secondary (N = 13) human liver tumor samples recovered by hepatectomy. The average attenuation coefficients of the primary and secondary liver tumors were 0.10 ± 0.03 and 0.20 ± 0.04 Np/cm/MHz, respectively. The average attenuation coefficients of the liver tissue surrounding the primary and secondary tumors were 0.16 ± 0.07 and 0.07 ± 0.02 Np/cm/MHz, respectively. Numerical simulations performed using these values revealed that completely different HIFU ablation patterns were created in primary and secondary liver tumors using the same exposure parameters. The dimensions of a typical HIFU lesion were two times larger in secondary liver tumors than in primary tumors. HIFU treatment parameters should be set properly according to the acoustic properties of the diseased liver tissue.

A Journey from Learning a Noninvasive High-intensity Focused Ultrasound Surgical Treatment for Gynecological Diseases to Providing High-intensity Focused Ultrasound Services in Hong Kong.

This paper reflects a Hong Kong doctors group's journey to learn the high-intensity focused ultrasound (HIFU) ablation treatment for gynecological diseases in China. The procedures of HIFU ablation for fibroids, adenomyosis, and other gynecological diseases are described. After completing our training, the authors applied the HIFU ablation techniques they have learned to establish an outpatient HIFU clinic and provided HIFU ablation treatment in Hong Kong. This paper describes their early experience in providing HIFU services.

Phase-shift Perfluoropentane Nanoemulsions Enhance Pulsed High-intensity Focused Ultrasound Ablation in an Isolated Perfused Liver System and Their Potential Value for Cancer Therapy.

To investigate whether phase-shift perfluoropetane (PFP) nanoemulsions can enhance pulsed high-intensity focused ultrasound (HIFU) ablation. PFP was encapsulated by poly(lactic-co-glycolic acid) (PLGA) to form a nanometer-sized droplet (PLGA-PFP), which was added to an isolated perfused liver system. Meanwhile, phosphate-buffered saline (PBS) was used as a control. The perfused liver was exposed to HIFU (150 W, t=3/5/10 s) at various duty cycles (DCs). The ultrasound images, cavitation emissions, and temperature were recorded. Rabbits with subcutaneous VX2 tumors were exposed to HIFU (150 W) at various DCs with or without PLGA-PFP. After ablation, necrosis volume and energy efficiency factor were calculated. Pathologic characteristics were observed. Compared to the PBS control, PLGA-PFP nanoemulsions markedly enhanced HIFU-induced necrosis volume in both perfused livers and subcutaneous VX2 tumor-bearing rabbits (P <.05). Inertial cavitation was much stronger in the pulsed-HIFU exposure at 10% than that in the continuous-wave HIFU exposure (P <.01). Peak temperature at 100% DC was significantly higher than that at 10% (P <.05). Compared to 100% DC HIFU exposure, the mean necrosis volume induced by 10 s exposure at 50% DC was significantly larger (P <.005) but lower at 10% DC in the isolated perfused livers (P <.05). In addition, the mean necrosis volume in subcutaneous VX2 tumor-bearing rabbits was significantly increased after HIFU exposure at 10% DC when compared to those at 100% DC (P <.05). Histopathologic analysis showed liquefaction necrosis in pulsed HIFU. PLGA-PFP nanoemulsions can enhance HIFU ablation in the isolated perfused livers and promote tumor ablation in the subcutaneous xenograft rabbit model. Appropriate pulsed HIFU exposure may increase the necrosis volume and reduce total ultrasound energy required for HIFU ablation.

Quantifying cell death induced by doxorubicin, hyperthermia or HIFU ablation with flow cytometry

Triggered release and targeted drug delivery of potent anti-cancer agents using hyperthermia-mediated focused-ultrasound (FUS) is gaining momentum in the clinical setting. In early phase studies, tissue biopsy samples may be harvested to assess drug delivery efficacy and demonstrate lack of instantaneous cell death due to FUS exposure. We present an optimised tissue cell recovery method and a cell viability assay, compatible with intra-cellular doxorubicin. Flow cytometry was used to determine levels of cell death with suspensions comprised of: (i) HT29 cell line exposed to hyperthermia (30 min at 47 °C) and/or doxorubicin, or ex-vivo bovine liver tissue exposed to (ii) hyperthermia (up to 2 h at 45 °C), or (iii) ablative high intensity FUS (HIFU). Flow cytometric analysis revealed maximal cell death in HT29 receiving both heat and doxorubicin insults and increases in both cell granularity (p < 0.01) and cell death (p < 0.01) in cells recovered from ex-vivo liver tissue exposed to hyperthermia and high pressures of HIFU (8.2 MPa peak-to-peak free-field at 1 MHz) relative to controls. Ex-vivo results were validated with microscopy using pan-cytokeratin stain. This rapid, sensitive and highly quantitative cell-viability method is applicable to the small masses of liver tissue typically recovered from a standard core biopsy (5–20 mg) and may be applied to tissues of other histological origins including immunostaining.

Stent Insertion With High Intensity-Focused Ultrasound Ablation for Biliary Obstruction Caused by Pancreatic Carcinoma: A Randomized Controlled Trial.

This study was designed to assess the clinical efficacy of stent insertion with high intensity-focused ultrasound ablation (HIFUA) in patients with malignant biliary obstruction (MBO) as a consequence of pancreatic carcinoma (PC). This was a single-center, open-label, prospective, randomized controlled trial. Consecutive patients with MBO caused by PC were randomly assigned to undergo stent insertion with or without HIFUA from June 2019 to February 2020. This study was registered at ClinicalTrials.gov (NCT03962478). In total, 92 patients were enrolled in this study and assigned to the stent-only (n=46) or combined (stent+HIFUA; n=46) treatment groups. Stent insertion was associated with a 100% technical success rate. For patients in the combination treatment group, 26, 18, and 2 patients underwent 2, 3, and 4 cycles of HIFUA, respectively. A positive clinical response to HIFUA treatment was noted in 38 patients (82.6%). Stent dysfunction was detected in 9 and 15 patients in the combination and stent-only groups, respectively (P=0.154), while median stent patency in these 2 groups was 188 and 120 days, respectively (P<0.001). All patients died over the course of the follow-up, with median survival periods of 218 and 140 days in the combination and stent-only treatment groups, respectively (P=0.001). The only detected predictor of prolonged survival was HIFUA treatment (P=0.004), and there were no significant differences in complication rates between these 2 treatment groups. A combination of stent insertion and HIFUA can improve stent patency and overall survival in patients suffering from MBO because of PC relative to stent insertion alone.

Analysis of the nonperfused volume ratio of adenomyosis from MRI images based on fewshot learning

The nonperfused volume (NPV) ratio is the key to the success of high intensity focused ultrasound (HIFU) ablation treatment of adenomyosis. However, there are no qualitative interpretation standards for predicting the NPV ratio of adenomyosis using magnetic resonance imaging (MRI) before HIFU ablation treatment, which leading to inter-reader variability. Convolutional neural networks (CNNs) have achieved state-of-the-art performance in the automatic disease diagnosis of MRI. Since the use of HIFU to treat adenomyosis is a novel treatment, there is not enough MRI data to support CNNs. We proposed a novel few-shot learning framework that extends CNNs to predict NPV ratio of HIFU ablation treatment for adenomyosis. We collected a dataset from 208 patients with adenomyosis who underwent MRI examination before and after HIFU treatment. Our proposed method was trained and evaluated by fourfold cross validation. This framework obtained sensitivity of 85.6%, 89.6% and 92.8% at 0.799, 0.980 and 1.180 FPs per patient. In the receiver operating characteristics analysis for NPV ratio of adenomyosis, our proposed method received the area under the curve of 0.8233, 0.8289, 0.8412, 0.8319, 0.7010, 0.7637, 0.8375, 0.8219, 0.8207, 0.9812 for the classifications of NPV ratio interval [0%–10%), [10%–20%), …, [90%–100%], respectively. The present study demonstrated that few-shot learning on NPV ratio prediction of HIFU ablation treatment for adenomyosis may contribute to the selection of eligible patients and the pre-judgment of clinical efficacy.

High-intensity focused ultrasound treatment as an alternative regimen for myxofibrosarcoma.

Myxofibrosarcoma is a common soft-tissue sarcoma in elderly patients, characterized by an infiltrative growth pattern and a high risk for persistent local recurrence. A 35-years-old woman was diagnosed with myxofibrosarcoma on the right upper arm and the tumor is surgically resected. The tumor relapsed 7 months later. Then the patient received five cycles of low power cumulative high-intensity focused ultrasound (HIFU) treatments, which completely ablated the tumor without complications. Now the patient is disease free with a high quality of life more than 30 months. This case indicates HIFU ablation might be a novel, promising therapy for recurrent myxofibrosarcoma.