METHODS: A bolus of fluorescently labeled mAb was given intravenously, followed by a slow infusion of microbubbles. Focused ultrasound delivers targeted immune cells to metastatic brain tumors. eCollection 2020. Interestingly, while this approach was demonstrated here for anti-CD73 mAb, our theranostic approach could be extended to other antibody based therapies, including checkpoint blockade, to increase their efficacy or alternatively to reduce the dose and associated side effects and cost. A recent study reported that combining UTMC with antibody check-point blockade (anti-PD-1) induced tumor growth inhibition and an increase in survival in the treated group [16], however the mechanism remains unclear, since there was no evidence of an increase in tumor infiltrating lymphocytes. Volume was calculated as (length × width × depth / 2). Fluorescence was measured in an infrared imaging system (700 nm, Odyssey, LI-COR). Whereas e.g. ... concept allows us to determine the location of an interface by measuring the elapsed time between the transmitted pulse ultrasound wave ad detected echoes from the interface? compound (Fisher Healthcare Tissue-Plus, Fisher Scientific company, Ottawa, Canada) for confocal microscopy imaging (Figure 1). Typically, we adjust the pulse width to half the period. Blue pixels in the resulting binary image located near each other were connected and defined as forming a vessel: this was obtained by sequentially filtering out noise (individual pixels) and performing two successive dilations: the first dilation (8 μm) was used to define the “inside” of the vessel; a second dilation (25 μm) was used to group closer agglomeration of cell nuclei into one continuous vessel. 4T1 tumors grew at similar rates in left and right sides (Figure 5) and were treated between days 12 and 17 when the individual tumor volumes reached a target size of 200-300 mm3. Sharma P, Allison JP. Example of confocal data image quantification: a) [DeltaAB] plotted as a function of distance for each vessel; b) [DeltaAB]max is projected to the right for each vessel; c) the extravasation range is projected to the bottom for each vessel, defined as the location where [DeltaAB]max reached its maximal value. For tumors, however, to the authors' knowledge, this is the first study describing the ability of UTMC to increase antibody accumulation and tumoral antibody extravasation in vivo outside the central nervous system and to provide detailed and simultaneous macroscopic and microstructural effects of UTMC therapy on antibody extravasation kinetics. Expert Rev Anticancer Ther. -, Vijayan D, Young A, Teng MWL, Smyth MJ. This site needs JavaScript to work properly. UTMC therapy (1 MHz, 850 kPa) was given under ultrasound image guidance for 5 minutes to the right side tumor only, using three different pulse lengths with identical ultrasound energy (5000cyc “long”, 125x40cyc “mid” and 500x10cyc “short”), and leaving the left tumor as a paired control. PD-1/PD-L1 and CTLA-4) in order to stimulate anti-tumor immune responses [3]. All animal protocols used in this study were approved by the CHUM research center Institutional Animal Protection Committee. Ultrasound • Ultrasound imaging is b ... = length of pulselength of pulse = (#cycles/pulse) n Frequency Pulse-Wave Parameters n Period Related to repeats itself temporal resolution = time pulse lasts Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. var thismailbody4 = ""; Maurer C, Qi R, Raghavan V. A Linear Time Algorithm for Computing Exact Euclidean Distance Transforms of Binary Images in Arbitrary Dimensions. In tumors, extracellular ATP is released in response to cellular stress [18] and gets degraded into adenosine by ecto-nucleotidases, notably by CD39 (hydrolyzing ATP to AMP) and CD73 (hydrolyzing AMP to adenosine). We were expecting differences since it is known that MB cavitation activity is higher with long pulses compared to shorter pulses [35-37]. gadolinium or Evan's blue) to antibodies (100 kDa) (e.g. For instance, high pressure UTMC (500 kHz, 100 ms duration, 1.4 MPa) caused an increase in heat shock protein expression and induced a T-cell immune response in a CT26 tumor model [14]. Epub 2020 Jun 14. This technology was shown to be safe in a first in-human study concluded recently [9] and to increase the delivery of many compounds to the brain, ranging from small molecular drugs (< 1 kDa) (e.g. Description. This allo… Ultrasound images of flow, whether color flow or spectral Doppler, are essentially obtained from measurements of movement. Differential extravasation ([DeltaAB]max) and extravasation range between UTMC-treated and non-treated tumors, for each US pulse and time point. It was intriguing to find that the biofluorescence data was maintained at 24 h whereas the confocal extravasated data largely decreased at 24 h. This could be explained by the contribution of antibodies from the blood pool to the biofluorescence signal, whereas blood was flushed at sacrifice for the confocal data. Confocal data analysis: (a) Differential extravasated antibody signal [DeltaAb]max; and (b) Extravasation range for each UTMC treatment as a function of side for each timepoint. Adenosine drives potent immunosuppressive signals on virtually all major immune cells [19] and are foreseen as the next generation of immune checkpoint inhibitors [5, 20]. 2018;35:691-705, 9. 1979;9:62-6, 23. Mathematically, it is the product of the number of cycles in a pulse and the wavelength. et al. What is pulse length? Echo ranging. Real-time ultrasound images are integrated images resulting from reflection of organ surfaces and scattering within heterogeneous tissues. Dependence of the reversibility of focused- ultrasound-induced blood-brain barrier opening on pressure and pulse length in vivo. Spatial pulse length in ultrasound imaging describes the length of time that an ultrasound pulse occupies in space. Herceptin), nanoparticles (20-50 nm), and even cells (several μm) [10-13]. Not Applicable. If an ultrasound system is used for imaging, it must use pulsed ultrasound and, therefor e, the duty factor must be between 0% and 100% (or 0 and 1), typically close to 0. Finally, this study results revealed macroscopic and microscopic evidence of tumoral antibody accumulation followed by UTMC are largely in line with other scientific reports and warrant further investigation to determine if UTMC can enhance antibody and immunotherapy efficacies. Tumors volumes ranged from 66 to 550 mm3 and were not larger on one particular side (Figure 5c). Pulse – A collection of ultrasound waves emitted by the transducer as a single ‘unit’ that travel together that are followed by a resting tim Typical value: 2 – 4 cycles in a pulse Pulse Duration – (PD) The amount of time from the beginning to the end of a single pulse of ultrasound (Time it takes for one pulse … Ultrasound Physics Formulas. Equation Spatial Pulse Length Definition The length or distance that a pulse occupies in space. 2020 Nov 18;15(11):e0242264. Clipboard, Search History, and several other advanced features are temporarily unavailable. We found that there was a preferential accumulation of mAb in our model on the side receiving UTMC immediately after therapy (0 h timepoint), and that this differential increase persisted for at least 4 h after therapy, except for the 5000cyc pulse, consistently with blood brain barrier opening literature. Frozen tumors were cryo-sectioned (5 μm), mounted (Prolong Gold, Invitrogen) and scanned using a confocal microscope (Leica TCS-SP5MP, 20x) to detect vessels (Hoechst) and antibodies (AF680) at respective (Ex/Em) wavelengths of (405 nm/460 nm) and (633 nm/682HP nm). This suggests that the increase in biofluorescence observed at the macroscopic level was caused by a modification at the microscopic level where antibodies could be found beyond the intravascular space and into the tumoral interstitium. 2017;7:3527-38, Corresponding author: Francois T.H. Heterogeneous distribution of trastuzumab in HER2-positive xenografts and metastases: role of the tumor microenvironment. Our online ultrasound physics trivia quizzes can be adapted to suit your requirements for taking some of the top ultrasound physics quizzes. Pulse Type: Two types of excitation pulses are commonly used in portable flaw detectors. Interestingly, confocal data supported that the highest extravasation range was obtained at 0 h with the long pulse and that the short pulse caused no increase in the extravasation range. 2. To capture the effect of time, the data was replotted for the three animals that were imaged longitudinally at all timepoints for each pulse in Figure 7. 14) Focal Zone The starting and ending points of the focal zone are located where the on-axis pulse-echo signal amplitude drops to - 6 dB of the amplitude at the focal point. 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