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OBJECTIVE: We aimed to investigate whether a current commercially available high-intensity focused ultrasound (HIFU) probe can adequately image targeted vascular malformations (VMs) in anticipation of HIFU treatment planning and delivery. METHODS: We enrolled 10 consecutive patients who were scheduled to undergo treatment of symptomatic peripheral VMs confirmed by routine preoperative contrast-enhanced magnetic resonance imaging and soft tissue duplex ultrasound. The lesions were situated no more than 6 cm from the skin. After induction of general anesthesia and before surgical intervention, we prepared and positioned the Sonablate HIFU probe (SonaCare Medical, LLC, Charlotte, NC) to obtain multiple B-mode images of the targeted VM in the transverse and longitudinal dimensions. We then rated the quality of the images and the feasibility of the imaging process itself using a previously devised questionnaire aimed at evaluating the adequacy of the images for potential HIFU treatment planning and delivery. The patients subsequently underwent surgical intervention and clinical follow-up for their VM per the standard protocol. RESULTS: The study included 10 participants aged 21 to 67 years (mean ± standard deviation, 36.5 ± 16.5 years). Six patients (60%) identified as female. The VMs imaged consisted of eight venous (80%), one lymphatic (10%), and one combined lymphovenous (10%) malformation. The lesions were in the extremities only (50%), trunk only (20%), trunk and extremities (20%), or neck and extremities (10%). Pain related to the VM was present in all 10 patients (100%). In all 10 patients, the boundary and location of the VM could be visualized via the HIFU probe despite the diminished B-mode imaging resolution. The absence of Doppler functionality in the HIFU probe did not prevent the identification of the VMs in any patient up to a depth of 6 cm. The results from the postimaging survey showed that difficulty in preparing the study device for imaging was 1.1 ± 0.3 and difficulty in use was 1.1 ± 0.1, with a score of 1 equal to easy and 5 to difficult. The stability of the acoustic coupling to the patient was 1.3 ± 0.2, with a score of 1 representing very stable. CONCLUSIONS: We were able to ultrasonically identify and outline all targeted peripheral VMs using a commercially available HIFU probe in anticipation of treatment planning and delivery. Baseline magnetic resonance imaging and soft tissue duplex ultrasound remain essential tools for guiding probe placement and HIFU imaging.
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Ultrassonografia de Intervenção , Malformações Vasculares/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Ultrassonografia de Intervenção/métodos , Adulto JovemRESUMO
BACKGROUND: The purpose of these clinical studies was to validate a Tissue Change Monitoring (TCM) algorithm in vivo. TCM is a quantitative tool for the real-time assessment of HIFU dose. TCM provides quantitative analysis of the backscatter pulse echo signals (pre and immediately post HIFU) for each individual ablative site, using ultrasonic tissue characterization as a surrogate for monitoring tissue temperature. Real-time analysis generates an energy difference parameter (ΔE in dB) that is proportional to tissue temperature. METHODS: Post in vitro studies, two clinical studies were conducted to validate the TCM algorithm on the Sonablate® device. Studies enrolled histologically confirmed, organ confined prostate cancer patients. The first clinical study was conducted in two phases for whole gland ablation. First eight patients' data were used to measure the algorithm performance followed by 89 additional patients for long term outcome. The second clinical study enrolled five patients; four patients with focal cancer had hemi-ablation only and one had whole gland ablation. Four 3 Fr. needles containing three thermocouples each were placed transperineally in the prostate to record tissue temperatures in the focal zone, posterior to the focal zone and on the lateral gland where no HIFU was applied. Tissue temperatures from the focal zone were correlated to the ΔE parameter. RESULTS: In the first clinical study, the average TCM rate was 86%. Pre and 6 months post HIFU, median PSA was 7.64 and 0.025 ng/ml respectively and 97% patients had negative biopsy. For the second clinical study, the measured prostate tissue temperatures (Average, Max, and Min) in the ablation zones were 84°, 114° and 60 °C and the corresponding ΔE (dB/10) parameters were 1.05, 2.6 and 0.4 resulting in 83% of temperatures in the range of 75°-100 °C and 17% in the 60°-74 °C range. Outside the focal zone, the average temperature was 50 °C and in the lateral lobe where no HIFU was applied, peak temperature was 40.7 °C. CONCLUSIONS: The TCM algorithm is able to estimate tissue changes reliably during the HIFU procedure for prostate tissue ablation in real-time and can be used as a guide for HIFU dose delivery and tissue ablation control.
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Localized gene delivery has many potential clinical applications. However, the nucleic acids (e.g. pDNA and siRNA) are incapable of passively crossing the endothelium, cell membranes and other biological barriers which must be crossed to reach their intracellular targets. A possible solution is the use of ultrasound to burst circulating microbubbles inducing transient permeabilization of surrounding tissues which mediates nucleic acid extravasation and cellular uptake. In this study we report on an optimization of the ultrasound gene delivery technique. Naked pDNA (200 µg) encoding luciferase and SonoVue® microbubbles were co-injected intravenously in mice. The hindlimb skeletal muscles were exposed to ultrasound from a non-focused transducer (1 MHz, 1.25 MPa, PRI 30s) and injection protocols and total amounts as well as ultrasound parameters were systemically varied. Gene expression was quantified relative to a control using a bioluminescence camera system at day 7 after sonication. Bioluminescence ratios in sonicated/control muscles of up to 101× were obtained. In conclusion, we were able to specifically deliver genetic material to the selected skeletal muscles and overall, the use of bolus injections and high microbubble numbers resulted in increased gene expression reflected by stronger bioluminescence signals. Based on our data, bolus injections seem to be required in order to achieve transient highly concentrated levels of nucleic acids and microbubbles at the tissue of interest which upon ultrasound exposure should lead to increased levels of gene delivery. Thus, ultrasound mediated gene delivery is a promising technique for the clinical translation of localized drug delivery.
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DNA/administração & dosagem , Técnicas de Transferência de Genes , Músculo Esquelético/metabolismo , Animais , Feminino , Infusões Intravenosas , Injeções , Luciferases/genética , Luminescência , Camundongos , Microbolhas , Músculo Esquelético/patologia , Plasmídeos , SonicaçãoRESUMO
Ultrasound-mediated delivery (USMD) of novel therapeutic agents in the presence of microbubbles is a potentially safe and effective method for gene therapy offering many desired characteristics, such as low toxicity, potential for repeated treatment, and organ specificity. In this study, we tested the capability of USMD to improve gene expression in mice livers using glycogen storage disease Type Ia as a model disease under systemic administration of naked plasmid DNA. Image-guided therapeutic ultrasound was used in two studies to provide therapeutic ultrasound to mice livers. In the first study, involving wild-type mice, control animals received naked plasmid DNA (pG6Pase 150 µg) via the tail vein, followed by an infusion of microbubbles; the treated animals additionally received therapeutic ultrasound (1 MHz). Following the procedure, the animals were left to recover and were subsequently euthanized after 2 d and liver samples were extracted. Reverse transcription polymerase chain reaction (RT-PCR) assays were performed on the samples to quantify mRNA expression. In addition, Western blot assays of FLAG-tagged glucose-6-phosphatase (G6Pase) were performed to evaluate protein expression. Ultrasound-exposed animals showed a 4-fold increase in G6Pase RNA in the liver, in comparison with control animals. Furthermore, results from Western blot analysis demonstrated a 2-fold increased protein expression in ultrasound-exposed animals after two days ( p < 0.05). A second pilot study was performed with G6Pase knockout mice, and the animals were monitored for correction of hypoglycemia over a period of 3 weeks before tissue analysis. The RT-PCR assays of samples from these animals demonstrated increased G6Pase RNA in the liver following ultrasound treatment. These results demonstrate that USMD can increase gene expression of systemically injected naked pDNA in the liver and also provide insight into the development of realistic approaches that can be translated into clinical practice.
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DNA/administração & dosagem , DNA/genética , Fígado/metabolismo , Microbolhas , Plasmídeos/administração & dosagem , Plasmídeos/genética , Transfecção/métodos , Ultrassom/métodos , Animais , Western Blotting , DNA/farmacocinética , Terapia Genética/métodos , Glucose-6-Fosfatase/química , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Fígado/química , Camundongos , Camundongos Knockout , Projetos Piloto , Plasmídeos/farmacocinéticaRESUMO
Glycogen storage disease type Ia (GSDIa) is caused by an inherited defect in the glucose-6-phosphatase gene. The recent advent of targeted ultrasound-mediated delivery (USMD) of plasmid DNA (pDNA) to the liver in conjunction with microbubbles may provide an alternative treatment option. This study focuses on determining the acoustically accessible liver volume in GSDIa patients using transducer models of various geometries with an image-based geometry-driven approach. Results show that transducers with longer focal lengths and smaller apertures (up to an f/number of 2) are able to access larger liver volumes in GSDIa patients while still being capable of delivering the required ultrasound dose in situ (2.5 MPa peak negative pressure at the focus). With sufficiently large acoustic windows and the ability to use glucose to easily assess efficacy, GSD appears to be a good model for testing USMD as proof of principle as a potential therapy for liver applications in general.
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Terapia Genética/métodos , Doença de Depósito de Glicogênio Tipo I/diagnóstico por imagem , Doença de Depósito de Glicogênio Tipo I/terapia , Terapia por Ultrassom/métodos , Ultrassonografia de Intervenção/métodos , Adolescente , Adulto , Algoritmos , Humanos , Imageamento Tridimensional/métodos , Microbolhas , TransdutoresRESUMO
Ultrasound transducers designed for therapeutic purposes such as tissue ablation, histotripsy, or drug delivery require large apertures for adequate spatial localization while providing sufficient power and steerability without the presence of secondary grating lobes. In addition, it is highly preferred to minimize the total number of channels and to maintain simplicity in electrical matching network design. To this end, we propose array designs that are both space-filling and non-periodic in the placement of the elements. Such array designs can be generated using the mathematical concept of non-periodic or aperiodic tiling (tessellation) and can lead to reduced grating lobes while maintaining full surface area coverage to deliver maximum power. For illustration, we designed two 2-D space-filling therapeutic arrays with 128 elements arranged on a spherical shell. One was based on the two-shape Penrose rhombus tiling, and the other was based on a single rectangular shape arranged non-periodically. The steerability performance of these arrays was studied using acoustic field simulations. For comparison, we also studied two other arrays, one with circular elements distributed randomly, and the other a periodic array with square elements. Results showed that the two space-filling non-periodic arrays were able to steer to treat a volume of 16 x 16 x 20 mm while ensuring that the grating lobes were under -10 dB compared with the main lobe. The rectangular non-periodic array was able to generate two and half times higher power than the random circles array. The rectangular array was then fabricated by patterning the array using laser scribing methods and its steerability performance was validated using hydrophone measurements. This work demonstrates that the concept of space-filling aperiodic/non-periodic tiling can be used to generate therapy arrays that are able to provide higher power for the same total transducer area compared with random arrays while maintaining acceptable grating lobe levels.
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Transdutores , Terapia por Ultrassom/instrumentação , Terapia por Ultrassom/métodos , Acústica , Simulação por Computador , Desenho de EquipamentoRESUMO
We investigated the preparation of ultrasound-triggered drug delivery system, based on a pendant complex of microbubble coated with liposomes. Biotinylated decafluorobutane microbubbles were coated with biotinylated liposomes via a streptavidin linker. Liposomes were prepared incorporating calcein and thrombin. Based on initial concentration of calcein, over 1 um(3) payload volume per each microbubble-liposome particle was achieved, when 100 nm liposomes were used. Insonation of microbubble-liposome pendants in vitro resulted in the complete destruction of microbubbles and triggered release of a significant fraction of the entrapped material. Treatment with 1MHz ultrasound (5 pulses, 100 ms, 7 MPa peak negative acoustic pressure) resulted in the release of ~30% of entrapped calcein, as estimated by the fluorescence quenching assay. Thrombin release from liposomes complexed with microbubbles (11% of entrapped material) due to ultrasound treatment was estimated by a chromogenic substrate study. Prior to insonation, substrate hydrolysis was at background level. Ultrasound-triggered release of thrombin from the pendant complexes caused an acceleration of blood clotting.
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Sistemas de Liberação de Medicamentos/métodos , Lipossomos , Microbolhas , Ultrassom , Animais , Cães , Fluoresceínas/administração & dosagem , Fluoresceínas/química , Fluorescência , Trombina/administração & dosagem , Trombina/químicaRESUMO
Ultrasound-mediated delivery (USMD) is an active research topic, as researchers develop applications for therapeutic ultrasound in addition to thermal ablation. In USMD, ultrasound is used in conjunction with microbubbles and drugs, nanoparticles, siRNA, pDNA, stem cells, etc., to facilitate their cellular delivery and uptake using pressure and temperature-mediated mechanisms to bring about a desired therapeutic effect. To investigate the potential of targeted USMD of nanoparticles, pDNA, and stem cells for cardiovascular and other applications, a general-purpose preclinical research tool, therapy imaging probe system (TIPS) was designed. It consists of a wideband annular array, a small-animal acoustic coupler, a motorized positioning system, integrated control software for ultrasound image-guided treatment planning and execution, and triggering electronics that allow ECG and respiration-gated ultrasound exposures. TIPS was then used to enhance delivery of nanoparticles into the murine myocardium and heart vessel walls to demonstrate the feasibility of the technology, pave the way for additional basic research in cardiovascular USMD, and begin to explore the requirements that USMD devices will have to meet to be useful in a clinical setting.
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Sistemas de Liberação de Medicamentos/métodos , Processamento de Imagem Assistida por Computador/métodos , Nanopartículas/administração & dosagem , Ultrassonografia/métodos , Animais , Sistemas de Liberação de Medicamentos/instrumentação , Ecocardiografia , Processamento de Imagem Assistida por Computador/instrumentação , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Software , Ultrassonografia/instrumentaçãoRESUMO
PURPOSE: High intensity focused ultrasound for renal lesions is still experimental. In a porcine model we evaluated the safety and efficacy of a newly designed laparoscopic high intensity focused ultrasound probe and software that allows real-time ultrasound guidance during renal tissue ablation. MATERIALS AND METHODS: A Sonatherm 600 high intensity focused ultrasound system with a newly designed laparoscopic high intensity focused ultrasound probe was used through a standard Endopath 18 mm port. A total of 16 lesions were created in 15 kidneys in a total of 8 animals and randomized into 2 groups, including acute with sacrifice 4 days postoperatively and subacute with sacrifice 14 days postoperatively. Lesion size and location varied for each surgical procedure to simulate various treatment scenarios. RESULTS: Mean +/- SD planned ablation volume was 7.1 +/- 5.1 cc and mean treatment time was 7.2 +/- 06.88 minutes. For all lesions an injury volume was observed with a central zone of complete necrosis and no viable tissue. Mean total injury volume was 6.5 + 3.5 cc (range 1.1 to 13.7), comparable to preoperative mean planned ablation volume (p = 0.84). Mean necrosis volume was 4.89 +/- 2.9 cc (range 0.8 to 10.5), appreciably lower than preoperative mean planned ablation volume (p = 0.33). Presence of the collecting system interposed with the treatment region did not impact the injury volume-to-planned ablation volume ratio or the necrosis volume-to-planned ablation volume ratio. No animals died before study completion. Two intraoperative complications occurred, including a back wall musculature burn and a ureteral burn. CONCLUSIONS: Laparoscopic high intensity focused ultrasound for renal tissue using the newly developed probe was feasible and efficacious. The ability to perform renal high intensity focused ultrasound through an 18 mm laparoscopic port offers a new alternative for renal tumor ablation.
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Ablação por Cateter/instrumentação , Nefropatias/cirurgia , Laparoscopia/métodos , Terapia por Ultrassom/métodos , Ultrassonografia de Intervenção/instrumentação , Animais , Ablação por Cateter/métodos , Modelos Animais de Doenças , Desenho de Equipamento , Segurança de Equipamentos , Feminino , Nefropatias/diagnóstico por imagem , Procedimentos Cirúrgicos Minimamente Invasivos/instrumentação , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Nefrectomia/métodos , Probabilidade , Distribuição Aleatória , Sensibilidade e Especificidade , Suínos , Ultrassonografia de Intervenção/métodosRESUMO
OBJECTIVE: High-intensity focused ultrasound (HIFU) permits targeted homogeneous ablation of tissue. The objective of this phase 1 study was to evaluate the feasibility of HIFU ablation of small renal tumours under laparoscopic control. PATIENTS AND METHODS: Ten kidneys with solitary renal tumours were treated with a newly developed 4.0 MHz laparoscopic HIFU probe. In the first two patients with 9-cm tumours, a defined marker lesion was placed prior to laparoscopic radical nephrectomy. In eight patients with a mean tumour size of 22 mm (range, 11-40), the tumour was completely ablated as in curative intent, followed by laparoscopic partial nephrectomy in seven tumours. One patient had post-HIFU biopsies and was followed radiologically. Specimens were studied by detailed and whole-mount histology, including NADH stains. RESULTS: Mean HIFU insonication time was 19 min (range, 8-42), with a mean targeted volume of 10.2 cm3 (range, 9-23). At histological evaluation both marker lesions showed irreversible and homogeneous thermal damage within the targeted site. Of the seven tumours treated and removed after HIFU, four showed complete ablation of the entire tumour. Two had a 1- to 3-mm rim of viable tissue immediately adjacent to where the HIFU probe was approximated, and one tumour showed a central area with about 20% vital tissue. There were no intra- or postoperative complications related to HIFU. CONCLUSION: The morbidity of laparoscopic partial nephrectomy mainly comes from the need to incise highly vascularized parenchyma. Targeted laparoscopic HIFU ablation may render this unnecessary, but further studies to refine the technique are needed.
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Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Laparoscopia , Terapia por Ultrassom/métodos , Adulto , Idoso , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Espiral , Resultado do TratamentoRESUMO
PURPOSE: We examined the safety and potential efficacy of transrectally delivered high intensity focused ultrasound for the full gland ablation of previously untreated localized prostate cancer. MATERIALS AND METHODS: A total of 20 patients with localized prostate cancer underwent 1 to 3 high intensity focused ultrasound treatments of the prostate. The primary outcome was safety and the secondary outcomes were prostate specific antigen, prostate biopsy and quality of life measures. RESULTS: A total of 19 patients had complete followup. Serious adverse events related to treatment were limited with the most common adverse event being transient urinary retention more than 30 days in duration in only 10% of patients. Rectal injury occurred in 1 patient. With 1 to 3 treatments 42% of the patients achieved prostate specific antigen less than 0.5 ng/ml and a negative prostate biopsy. CONCLUSIONS: High intensity focused ultrasound in patients with previously untreated prostate cancer is generally well tolerated and it has the potential to completely ablate the prostate gland. With further refinement of the optimal treatment dose and technique this technology has the potential to be an effective form of therapy for localized prostate cancer.
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Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/terapia , Ultrassom Focalizado Transretal de Alta Intensidade/métodos , Idoso , Biópsia por Agulha , Estudos de Viabilidade , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Medição de Risco , Resultado do Tratamento , UltrassonografiaRESUMO
Current planning methods for transrectal high-intensity focused ultrasound treatment of prostate cancer rely on manually defining treatment regions in 15-20 sector transrectal ultrasound (TRUS) images of the prostate. Although effective, it is desirable to reduce user interaction time by identifying functionally related anatomic structures (segmenting), then automatically laying out treatment sites using these structures as a guide. Accordingly, a method has been developed to effectively generate solid three-dimensional (3-D) models of the prostate, urethra, and rectal wall from boundary trace data. Modeling the urethra and rectal wall are straightforward, but modeling the prostate is more difficult and has received much attention in the literature. New results presented here are aimed at overcoming many of the limitations of previous approaches to modeling the prostate while using boundary traces obtained via manual tracing in as few as 5 sector and 3 linear images. The results presented here are based on a new type of surface, the Fourier ellipsoid, and the use of sector and linear TRUS images. Tissue-specific 3-D models will ultimately permit finer control of energy deposition and more selective destruction of cancerous regions while sparing critical neighboring structures.