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Illustration of high-intensity focused ultrasound (HIFU) treatment of a pancreatic tumor from an extracorporeal HIFU system (Reproduced with permission from Dubinsky et al., AJR Am J Roentgenol 2008;190:191-199.). 

Illustration of high-intensity focused ultrasound (HIFU) treatment of a pancreatic tumor from an extracorporeal HIFU system (Reproduced with permission from Dubinsky et al., AJR Am J Roentgenol 2008;190:191-199.). 

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Article
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High-intensity focused ultrasound (HIFU) is a novel therapeutic modality that permits noninvasive treatment of various benign and malignant solid tumors, including prostatic cancer, uterine fibroids, hepatic tumors, renal tumors, breast cancers, and pancreatic cancers. Several preclinical and clinical studies have investigated the safety and effica...

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... treatment is non-invasive with ultrasound energy delivered from an extracorporeal source (Fig. 1). There have been several case series reporting on the use of HIFU to treat patients with pancreatic cancer (Table 1). 5,6,[13][14][15][16][17][18][19] These reports, all from China, investigated the use of HIFU as monotherapy or as combination therapy with chemotherapy. In general, these reports suggest that HIFU is an effective therapy for palliation of pain related to pancreatic cancer. Furthermore, no significant adverse effects were reported in any of these studies. The mecha- nism of pain relief in these patients is still unclear but may be due to damage of nerve fibers innervating the tumor. In these reports objective tumor response rates ranged from 14.6% to 74% with some cases showing sig- nificant reduction of tumor volume. However, there have been no comparative studies performed to demonstrate that treatment with HIFU confers a survival benefit. ...

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High-intensity focused ultrasound (HIFU) relies on the absorption of ultrasound irradiation to non-invasively cause thermal ablation of a tumor. We developed the cavitation suppression technique (CAST) to minimize the risks of non-target tissue damage during HIFU. This study examined the accurate focusing of the ultrasound beam to achieve precise l...

Citations

... 12 However a meta-analysis of randomized controlled trials of NCPB study reported that the overall advantage was lesser and there is only 6% pain reduction in the mean visual analogue pain score compared with baseline pain score. 13 14,15 In this technique, the temperature is controlled between certain degree centigrade so it should not cause an immediate necrosis of the cancer cells, but firstly it causes intracellular denaturation of protein, and thus of the stored pancreatic enzymes, followed by cellular degeneration and necrosis. In H I F U t e c h n i q u e , t h e r m a l f i x a t i o n phenomenon efficiently reduces the risk of pancreatitis as a complication of the procedure. ...
... In H I F U t e c h n i q u e , t h e r m a l f i x a t i o n phenomenon efficiently reduces the risk of pancreatitis as a complication of the procedure. 15 Besides the thermal effects of HIFU, there are also mechanical effects generated by high intensity acoustic energy that cause cavitation, micro-streaming and radiation force. Cavitation effects is generated from the oscillating motion of gasfilled bubbles (stable cavitation); these bubbles coalesce and collapse under higher ultrasound field energy, causing a shock wave confined to the microenvironment (inertial cavitation). ...
... 24 This effect was also reported by another study and they concluded that HIFU improve the therapeutic effect of chemotherapy in the patients with pancreatic carcinoma. 15 ...
Article
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Background: Day by day, High-intensity focused ultrasound (HIFU) therapy is becoming more familiar in medical field because it is non-invasive technique with fewer side effects and provides promising therapeutic results. Several HIFU therapy applications have approved by many approval authorities of deferent countries since last decade. It is a novel, emerging, therapeutic modality that uses ultrasound waves, propagated through tissue media, as carriers of energy. HIFU has great potential for tumor ablation and the main mechanisms of HIFU ablation involve mechanical and thermal effects. Pancreatic adenocarcinoma is currently the fourth-leading cause of cancer-related death. Up to 60–90% of patients with advanced disease suffer cancer-related pain, severely impacting their quality of life. Current management involves primarily pharmacotherapy with opioid narcotics and celiac plexus neurolysis; unfortunately, both approaches offer transient relief and cause undesired side-effects. High intensity focused ultrasound (HIFU) is a non-invasive thermal ablation technique that has been used to treat pancreatic cancer. This meta-analysis aims to evaluate the role of HIFU in pain palliation of advanced unresectable pancreatic adenocarcinoma. Methods: Paper selection was performed electronically in PubMed up to the end of March 2021, for pain palliation treatment of advanced staged pancreatic cancer with HIFU. Relevant papers were identified through the PubMed search engine using these keywords: HIFU, pancreas, pancreatic cancer, pain and palliation. Additional studies were also done included after manual search of the selected bibliographies. Palliation results reported in studies were analyzed using a logit-transformed random-effects model using the inverse variance method, with the DerSimonian-Laird estimator for t2, and Cochran’s Q test for heterogeneity among studies. The I2 was also calculated to assess the percentage of the total variability in the different effect size estimates that can be attributed to heterogeneity among the true effects and rank correlation test of funnel plot asymmetry was done to assess possible publication bias. Results: In this meta-analysis, we includes only recent 10 year studies i.e. total number of 16 studies with 687total patients with pancreatic cancer. The total patients enrolled ranges from 7 patients in the smallest series, up to 120 in the largest study. The calculated τ2was 0.187, and I2was 41%, the Q test p-value was 0. 026, is indicating significant heterogeneity among studies. The random effects estimate of the proportion of patients with pain reduction was 0.89.08. Conclusions: We concluded that HIFU performs to be an effective tool for pain palliation in advanced staged pancreatic cancer. Prospective randomized and standardized studies are necessary to confirm the effectiveness of HIFU in relieving pain, and to evaluate for any potential impact on tumor control and patient survival.
... Given the poor prognosis of patients with locally advanced pancreatic cancer, it is crucial to develop novel treatment modalities that enhance survival and quality of life. High-intensity focused ultrasound (HIFU) has emerged as a promising non-invasive imaging-guided thermal ablation technique inducing thermal and mechanical energy to the targeted tumor tissue, without affecting the surrounding healthy tissue [7,8]. HIFU is guided by other imaging modalities such as CT (Computed Tomography guided Focused Ultrasound-CTgFUS) or MRI (Magnetic Resonance guided Focused Ultrasound-MRgFUS) to enable guidance of the treatment and monitoring. ...
... The physiologic background that explains these findings is that PDAC is a relatively hypovascular tumor, enclosed by a fibrous ring that limits the penetration and diffusion of chemotherapeutic agents. In this context, HIFU might provide a synergistic effect with chemotherapy, through increased vascular permeability, thus boosting the drug concentration in the tumor microenvironment [8]. Furthermore, our study indicated that HIFU inhibits tumor progression, as evaluated by CA19-9 levels and tumor volume. ...
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Background This study aimed to evaluate the outcomes of high-intensity focused ultrasound (HIFU) on patients with advanced pancreatic cancer.MethodsA literature search was performed in PubMed, Scopus and Cochrane databases, in accordance with the PRISMA guidelines. The Odds Ratio, Weighted Mean Difference, and 95% Confidence Interval were evaluated by means of the Random-Effects model.ResultsNineteen articles met the inclusion criteria, incorporating 939 patients. This study reveals that patients in the HIFU group presented increased median overall survival (OS), along with higher OS at 6 and 12 months after treatment compared with the control group (p < 0.05). Furthermore, patients treated with HIFU in conjunction with chemotherapy presented reduced levels of pain (p < 0.05) compared to the traditional treatment group. In addition, HIFU contributed to significant tumor responsiveness, in terms of CA19-9 reduction (p < 0.05). Finally, HIFU was a considerably safe treatment modality with a low incidence of complications.Conclusion These outcomes suggest that HIFU is a feasible and safe treatment modality for patients with advanced pancreatic cancer and provides enhanced outcomes regarding survival and quality of life. Given the lack of a significant number of randomized clinical trials, this meta-analysis represents the best currently available evidence. New randomized trials assessing HIFU are necessary to further evaluate their outcomes.Graphic abstract
... In HIFU therapy, high-intensity acoustic waves are tightly focused at a targeted region of the tumor, resulting in either thermal or mechanical effects that may kill the tumor cells. With a high duty cycle, thermal HIFU relies on the absorption of acoustic energy, which results in high temperature rise [2] and tumor ablation [3][4][5][6][7][8]. With a low duty cycle, mechanical HIFU relies on pressure-induced acoustic cavitation, which can result in long-term anti-cancer immune response through cavitation-induced mechanical lysis and endogenous danger signals [9,10]. ...
Article
Mechanical high-intensity focused ultrasound (HIFU) has been used for cancer treatment and drug delivery. Existing monitoring methods for mechanical HIFU therapies such as MRI and ultrasound imaging often suffer from high cost, poor spatial-temporal resolution, and/or low sensitivity to tissue's hemodynamic changes. Evaluating vascular injury during mechanical HIFU treatment, therefore, remains challenging. Photoacoustic computed tomography (PACT) is a promising tool to meet this need. Intrinsically sensitive to optical absorption, PACT provides high-resolution imaging of blood vessels using hemoglobin as the endogenous contrast. In this study, we have developed an integrated HIFU-PACT system for detecting vascular rupture in mechanical HIFU treatment. We have demonstrated singular value decomposition for enhancing hemorrhage detection. We have validated the HIFU-PACT performance on phantoms and in vivo animal tumor models. We expect that PACT-HIFU will find practical applications in oncology research using small animal models.
... Ultrasound has a high spatial resolution and can deliver stimuli to precise locations even deep in the body [21]. Besides, ultrasound has already been used in actual medical practice for thermal treatment [22], imaging [23], and stone crushing [24], so its high affinity for medicine is confirmed. Generally, the principle of the ultrasound-triggered release of drugs has been mainly caused by cavitation including stable cavitation, inertial cavitation, and sonoporation [21,25]. ...
Article
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Ultrasound-triggered drug delivery has been widely researched for its potential to improve the therapeutic efficacy of a drug. This paper presents drug release using hydrogel microbeads with release enhancer for efficient ultrasound-triggered drug delivery. By using a centrifuge-based microfluidic device, drug-model-encapsulating calcium alginate hydrogel microbeads containing tungsten particles with high acoustic impedance were fabricated. Because the tungsten particles work as release enhancer, the hydrogel microbeads become to have high sensitivity to ultrasound with localized variation in acoustic impedance so that the release rate of drug models improves. By applying ultrasound to the hydrogel microbeads, the release of fluorescent silica nanoparticles that are a drug model for virus vectors, micelles, and proteins was tested. Importantly, the proposed hydrogel microbeads released the drug model even under a cavitation-suppressed environment. Furthermore, the additional coating on the hydrogel microbeads with poly-l-lysine enabled us to adjust the release rate of the drug model. The proposed ultrasound-triggered drug release system using release enhancer would be an effective approach for expanding the varieties of applicable treatments using on-demand drug delivery systems.
... 12 Since the 1950s, HIFU has been investigated in the management of various benign and malignant solid tumors. 13 Uses have extended to uterine fibroids, cesarean scar pregnancy, and adenomyosis. [14][15][16] Recently, HIFU has been proposed as a non-invasive treatment that could preserve the uterus in women with PAS without increasing surgical morbidity and risk of significant blood loss. ...
Article
Background: High intensity focused ultrasound (HIFU) is a non-invasive procedure that has been studied in management of placenta accreta spectrum (PAS). Objective: To appraise HIFU in management of PAS and highlight restrictions of transitioning uterus-preserving studies to practice. Search strategy: A search on Scopus, Cochrane, PubMed and Web of Science was conducted from date of inception to January 2020. Selection criteria: Studies on using HIFU in management of PAS were eligible. Review articles, conference papers, and case reports were excluded. Data collection: A standardized sheet was used to abstract data from eligible studies. CON-PAS registry was used to include studies on other conservative modalities. Results: Four studies were eligible (399 patients). Average residual placental volume was 61.74 cm3 (6.01-339). Treatment was successful in all patients. Normal menstruation recovered after 48.8 days (15-150). No major complications were encountered. Sixty-one studies were retrieved from CON-PAS registry; uterine artery embolization (23 studies), balloon placement (15), compression sutures (10), placenta in situ (7), and uterine resection (6) were successful in 83.7% 92.9% 87.9%, 85.2%, and 79.3%, respectively. Conclusions: HIFU may fit certain clinical situations in management of PAS. A global research strategy is recommended to incorporate conservative approaches within a comprehensive management protocol.
... Thermal ablation, the most clinically advanced bioeffect of focused ultrasound, produces cell death in a targeted area with minimal damage to the surrounding tissue [132,133]. ...
Thesis
Drug encapsulation is a thriving area where potential therapeutic improvements are important. In this regard, the ability to control drug release using ultrasound is attractive because it helps to locate and manage drug delivery. In my thesis project, I studied the possibility of using low ultrasonic intensities to control drug release. To do this, I used emulsions to encapsulate two types of drugs: "paclitaxel", an anticancer drug, and "levofloxacin", an antibiotic. Paclitaxel was encapsulated in an emulsion composed of nanodroplets comprising a core composed of oil and perfluorooctyl bromide (PFOB) stabilized by a fluorinated and biocompatible surfactant called Dendritac. Levofloxacin was encapsulated in an emulsion composed only of oily nanodroplets; we were able to reduce the diffusion of levofloxacin out of the droplet by adding esters of triglycerides. We investigated the ultrasound-triggered delivery of paclitaxel in the presence of a colorectal carcinoma cell line and levofloxacin in the presence of Escherichia coli. We have shown that ultrasound triggers the delivery of drugs for low sound pressures (0.4 Mpa) when using ultrasound at a frequency of 1 MHz with a duty cycle of 5% and a pulse repetition frequency of 200 Hz.
... A transducer with a bandwidth of at least 125-150% is therefore required; however, conventional piezoceramic transducers have a bandwidth limitation of ∼100%. The bandwidth limitation is also a challenge for diagnostic imaging using the third, and higher, harmonics [3]; when designing combined imaging and therapy systems [4]; and for new applications such as SURF [5]. ...
... II. COUPLED RESONATOR TRANSDUCER In Fig. 1, a schematic of the coupled resonator transducer (CRT) is shown. The CRT is comprised of two identical piezoceramic layers stacked on top of each other with a soft (2)(3)(4)(5) polymeric coupling layer sandwiched in between the active layers. The polarisation direction of the two active layers (which can be a solid piezoceramic, a piezopolymer composite, or elements in an array transducer) are reversed. ...
Article
New ultrasound mediated drug delivery systems, such as Acoustic Cluster Therapy, or combined imaging and therapy systems, require transducers that can operate beyond the bandwidth limitation (~100%) of conventional piezoceramic transducers. In the current paper, a dual-frequency coupled resonator transducer (CRT) comprised of a polymeric coupling layer with a low acoustic impedance (2-5 MRayl) sandwiched between two piezoceramic layers is investigated. Depending on the electrical configuration, the CRT exhibits two usable frequency bands. The resonance frequency of the high-frequency (HF) band can be tailored to be ~3-5 times higher than the resonance frequency of the low-frequency (LF) band by means of the stiffness in the coupling layer. The CRT’s LF band was analysed analytically and we obtained closed-form expressions for the LF resonance frequency. A dual-frequency CRT was designed, manufactured, and characterized acoustically and comparisons with theory showed good agreement. The HF band exhibited a centre frequency of 2.5MHz with a -3 dB bandwidth of 70%, and is suited to manipulate microbubbles, or for diagnostic imaging applications. The LF band exhibited a centre frequency of 0:5MHz with a -3 dB bandwidth of 13%, and is suited to induce biological effects in tissue, therein manipulation of microbubbles.
... Previous studies have demonstrated that the biological effects induced by ultrasound are primarily caused by thermal effects, inertial cavitation and ROS accumulation (12,39). Thermal effects and inertial cavitation may cause protein denaturation and tissue damage (39,40). The association between ultrasound treatment and ROS production has attracted increasing attention (41). ...
Article
Hepatocellular carcinoma (HCC) is a type of liver cancer and is a leading cause of cancer‑associated mortality. In China, ~466,000 patients are diagnosed with HCC and it is responsible for ~422,000 cases of mortality each year. Surgery is the most effective treatment available; however it is only suitable for patients with early‑stage HCC. Chemotherapy has been confirmed as a necessary treatment for patients with advanced HCC, although drug resistance may limit its clinical outcome. Low intensity ultrasound (LIUS) represents a novel therapeutic approach to treat patients with HCC; however, its underlying molecular mechanism remains unclear. In the present study, cell viability, apoptosis and reactive oxygen species (ROS) generation were determined via Cell Counting Kit‑8, flow cytometry and 2',7'‑dichlorofluorescein diacetate assays, respectively. The expression of miRNA in HCC cells following exposure to LIUS and doxorubicin (Dox) was analyzed using a microarray and reverse transcription‑quantitative polymerase chain reaction analysis. It was revealed treatment with LIUS in combination with Dox was able to induce apoptosis of Huh7 cells, increasing the intracellular levels of reactive oxygen species (ROS) and malondialdehyde. Glutathione peroxidase and superoxide dismutase 1 are ROS‑scavenging enzymes, which serve important roles in the oxidative balance, preventing oxidative stress. The protein expression levels of these two enzymes were significantly decreased following treatment with LIUS combined with Dox. The present results suggested that LIUS may decrease Dox resistance in HCC cells and that LIUS may be combined with chemotherapy to treat HCC. By performing microarray analysis, the expression levels of microRNA‑21 (miR‑21) were decreased following treatment with LIUS combined with Dox. Functional experiments showed that knockdown of miR‑21 enhanced the antitumor activity of Dox, whereas overexpression of miR‑21 reversed these effects. Phosphatase and tensin homolog (PTEN), a well‑known tumor suppressor, was revealed to be a direct target of miR‑21, and its translation was suppressed by miR‑21. Finally, it was determined that combined treatment of LIUS and Dox induced anticancer effects by blocking the activation of the AKT/mTOR pathway, as demonstrated by the downregulation of phosphorylated (p‑)AKT and p‑mTOR; N‑acetylcysteine, a general ROS inhibitor reversed the suppressive effects on the AKT/mTOR pathway mediated by LIUS and Dox. Collectively, the present results suggested that LIUS increased cell sensitivity to Dox via the ROS/miR‑21/PTEN pathway. Chemotherapy combined with LIUS may represent a novel effective therapeutic strategy to treat patients with advanced HCC.
... Lezyonlu dokuya HIFU uygulandığında termal ve mekanik etkiler ile hücre ölümü gerçekleştirilerek tedavi yapılmaktadır [4,5]. Günümüzde HIFU, tiroid, prostat, meme, pankreas ve karaciğer gibi organlardaki lokal hastalıkları tedavi etmek için çeşitli çalışmalar ve klinik uygulamalar sürdürülmektedir [6][7][8][9]. 2011 yılında yapılan bir çalışmada, HIFU kaynaklı doku hasarının pasif akustik incelenmesi için çalışmalar yapılmıştır. 1.067 MHz HIFU kullanarak öküz karaciğerinde uygulamalar yapılmıştır. ...
Conference Paper
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Today, cancerous tissues are an important problem that threatens human health. Many methods are used for the diagnosis and treatment of these tissues. High Intensity Focused Ultrasound (HIFU) technique is one of these methods. Commonly used treatment methods have many side effects. The use of HIFU in the treatment of cancer, non-invasive treatment, minimal environmental tissue damage, minimal side effects, radiation-free treatment, painless treatment, reproducibility, complete and effective results in one application, short-term hospitalization, low probability of complications it has many important advantages over the more common treatment methods.When performing HIFU treatment, it is important to calculate the extent of damage to surrounding tissues due to mechanical effect and increased heat. The amount and duration of ultrasound power must be accurately determined for safe application. In this study, 1.1 MHz frequency HIFU waves were applied experimentally on ex vivo calf liver in 80-135 W ultrasound power range and 10-30 sec application times. The images obtained from the experiments were analyzed in MATLAB using image processing techniques.
... At lower intensities, these regimens can give rise to subablative heating, i.e. hyperthermia, which is characterized by the predominance of non-lethal heat stress signatures. Meanwhile, mechanical FUS leads to acoustic cavitation, acoustic streaming/microstreaming, radiation force, and shear stresses within the pulsed acoustic field [16]. At high intensities, these bioeffects cause mechanical lysis of cells with minimal temperature rise; mechanical lesioning often results in subcellular fragmentation with sharply delineated margins [16]. ...
... Meanwhile, mechanical FUS leads to acoustic cavitation, acoustic streaming/microstreaming, radiation force, and shear stresses within the pulsed acoustic field [16]. At high intensities, these bioeffects cause mechanical lysis of cells with minimal temperature rise; mechanical lesioning often results in subcellular fragmentation with sharply delineated margins [16]. In the presence of systemically circulating microbubbles (MB), the intensity threshold required to achieve these cavitation effects within the tissue is lowered. ...
Article
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Immunotherapy holds tremendous promise as a strategy for eradicating solid tumors. However, poor T cell infiltration and persistence within most solid tumor microenvironments, as well as mechanisms of adaptive resistance, continue to severely limit the accessibility of most immunotherapies to a broad patient population. This limitation perpetuates the demand for allied therapeutic strategies. Among such strategies is focused ultrasound (FUS), a non-invasive, non-ionizing technique for precisely targeted acoustic energy deposition into tissues. FUS has gained remarkable attention over recent years as a modality for elicitation of immune mechanisms in cancer and other pathologies. In 2017, we published a comprehensive review paper detailing existing evidence for immune modulation and therapy with FUS, as well as impending challenges and opportunities of consideration for the field. Over the last two years, a multitude of clinical trials have come online to explore safety, feasibility, and efficacy of FUS for cancers of the brain and periphery - including the first clinical trial to combine FUS with immunotherapy. Moreover, the last two years have seen a surge in FUS immunotherapy presentations at therapeutic ultrasound scientific meetings. Given the burst of activity in this field, we submit that an update on FUS immunotherapy progress is timely. In this review, we offer an updated overview and perspectives on scientific and clinical development in the FUS immunotherapy domain.