Yu1,2. In this study, we hypothesized that UTMC could improve the accumulation and biodistribution of mAb targeting the adenosinergic pathway (i.e. Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing.Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. 2020, 5. 2019 Sep 21;9(23):7088-7098. doi: 10.7150/thno.34895. Number of extravasated and not extravasated vessels found by confocal microscopy. The time from the start of one pulse to the start of the next What is pulse length? Nat Rev Cancer. Science. Mammary carcinoma tumor cells (4T1), kindly provided by Dr Stagg (CRCHUM), were cultured in RPMI 1640 medium, supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin and passaged before reaching confluence (<80%). More specifically, we provide the first evidence that we can enhance the delivery of a mAb targeting the CD73 pathway in 4T1 cells, which may open interesting therapeutic perspectives for increasing the efficacy of this particular immunotherapy strategy. vessel with a positive [DeltaAB]. Science. Antibody injection time was the reference time (t=0 h) for the experiment. -, Sharma P, Allison JP. We foresee that improving the distribution of anti-CD73 mAb could contribute to reduce adenosine and therefore stimulate the immune system against tumor cells and could help overcome the limited number of patients responsive to check point inhibition. 2017;24:15, 3. Not Applicable. 2019;13:33-51, 31. Fluorescence was measured in an infrared imaging system (700 nm, Odyssey, LI-COR). A Euclidean distance transform (a map of the distance between each pixel and its nearest non- zero pixel [23]) was applied to the 'inside' vessel mask to draw a series of masks delimiting increasing distances away from the closest vessel. Total Cards. 2014;11:711-21, 13. Recently, using dorsal window chambers and two-photon microscopy, it was shown that UTMC dramatically increased the extravasation of 2 MDa FITC dextrans and nanoparticles in a human osteosarcoma model [15]. Ultrasound Targeted Microbubble Cavitation (UTMC) has been shown to increase vascular permeability and improve the delivery of therapeutic compounds including small molecules, antibodies (mAb), nanoparticles and even cells, notably across the blood-brain-barrier (BBB). Overall, the biofluorescence data suggests that UTMC caused an increased accumulation of antibody in the treated tumor at 0 h and 4 h but this effect was not detected at 24 h post UTMC. 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. In this study, we hypothesized that UTMC would enhance anti-CD73 mAb accumulation and tumoral distribution in the 4T1 murine mammary carcinoma model. The best axial resolution can be achieved is half of the pulse length. 4T1 cells (1×106) were mixed (1:1vol) with Matrigel matrix (Corning, Tewksbury, MA) and implanted subcutaneously and bilaterally into 8-10 weeks old female BALB/c mice (Charles Rivers) in the posterior upper flank area (100 μL/side). Heath CH, Sorace A, Knowles J, Rosenthal E, Hoyt K. Microbubble therapy enhances anti-tumor properties of cisplatin and cetuximab in vitro and in vivo. Maurer C, Qi R, Raghavan V. A Linear Time Algorithm for Computing Exact Euclidean Distance Transforms of Binary Images in Arbitrary Dimensions. Resolution in Ultrasound Imaging Axial Resolution: –Resolution in propagation direction –Determined by length of pulse propagating in tissue Axial Lateral Resolution: –Resolution orthogonal to – Determined by focusing properties of transducer Lateral Axial Resolution Axial Resolution: Axial Resolution = pulse width (s) x speed of sound (m/s) /2 BASED ON PULSE-ECHO PRINCIPLE. Pulses of high-frequency sound waves are transmitted to the patient. The red mask (a low-intensity threshold filter using Otsu's method) was necessary to eliminate integrating the red channel's noise. Nevertheless, much remains to be understood about the effect of MBs and ultrasound on antibody accumulation in solid tumors, including its spatial distribution and temporal kinetics. [16, 17]. The timing of this function has been determined empirically and will probably show errors in longer pulses. … The ultrasound waves are produced in pulses. 2018;35:691-705, 9. Ultrasound and Microbubble-targeted Delivery of a microRNA Inhibitor to the Heart Suppresses Cardiac Hypertrophy and Preserves Cardiac Function. The hydrophone comprises a minimum of 20 elements, linearly separated with an active length not exceeding 32.8 ft(10 m), with a flat frequency response across the 100 to 2000 Hz bandwidth. Subject. We thus decided to use the highest possible pressure available in our setup, namely 850 kPa. A comprehensive database of more than 13 ultrasound physics quizzes online, test your knowledge with ultrasound physics quiz questions. Echoes from stationary tissue are the same from pulse to pulse. The ultrasound therapeutic pulsing scheme differed significantly between these studies in terms of pressure, total number of cycles, treatment duration and most importantly pulse length. 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. A total of 27 mice were used in this study, 3 mice per group x 3-time points x 3 ultrasound pulses. Chang Gung Med J. 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 … At 0 h and 4 h, antibodies appeared to be restricted to the vascular space in tumors that did not receive UTMC. ClinCancer Res.  |  Each pulse is 2-3 cycles of the same frequency. Volume was calculated as (length × width × depth / 2). We found that all three tested US pulses caused an increased proportion of vessels to allow antibody extravasation (defined as the difference between extravascular and intravascular antibody fluorescent signal) at 0 h and 4 h, but not at 24 h (Table 2). gadolinium or Evan's blue) to antibodies (100 kDa) (e.g. Alkins R, Burgess A, Ganguly M, Francia G, Kerbel R, Wels WS. Finally, while our study demonstrated the effects of UTMC on anti-CD73 mAb delivery in tumors, it is reasonable to think that our findings may be extended to other antibody-based therapies where ultrasound imaging is suitable. Heterogeneous distribution of trastuzumab in HER2-positive xenografts and metastases: role of the tumor microenvironment. All calculations were done in MATLAB. Whereas e.g. Therefore binding of anti-CD73 mAbs to CD73 may lead to internalization and degradation of the antibody, although this was not demonstrated. Interestingly, short and long pulses have been used in the BBB literature and we therefore designed our experimental conditions to explore different pulse lengths, but with the same total acoustical power and number of cycles. The adenosine pathway in immuno-oncology. Indeed, higher pressure and/or MB cavitation can cause sterile inflammation in the brain, which could be a desirable bioeffect in the context of immunotherapy. CD73) in mice bearing bilateral subcutaneous 4T1 mammary carcinoma. Multiple comparisons analysis to discern differences between groups was performed using Sidak's post-hoc testing (Prism 8.0, Graphpad software, LaJolla, CA). Ultrasound Med Biol. Therapeutic US was delivered on the right tumor for 5 minutes using a single element commercial unfocussed transducer (1 MHz, 0.5 inch, A303S, Olympus), under live guidance using contrast enhanced US (CEUS) imaging (CPS7, Sequoia, Siemens), whereas the left tumor served as a paired control. Pulse duration does not change with depth, thus it cannot be changed by the sonographer. shell compositions, bubble size and gas type) correlate with the type and intensity of cavitation . 2017;17:527-35, 21. There are a few limitations to the findings reported in this study. Focused ultrasound with microbubbles induces sterile inflammatory response proportional to the blood brain barrier opening: Attention to experimental conditions. Interestingly, the short pulse (500x10cyc) did not cause an increase in extravasation range despite having a modest effect on [DeltaAb]max and increasing the fraction of extravasated vessels. Interestingly, UTMC has been shown to increase the extravasation of 60 kDa FITC dextran in xenografted mouse CT26 tumor model [14]. ; image guided therapy; immune check-point blockade; microbubbles; solid cancer; ultrasound. This work was funded by the Quebec Bio-Imaging Network (Initiatives Stratégiques #35450), by the Fonds de recherche du Québec - Santé (#265499), and by Start-up funds from the Centre de recherche du Centre hospitalier de l'Université de Montréal. Three tumors were analyzed for each group (excepted for the 500x10cyc group at 4 h, in which the Hoechst stain perfusion failed in one mouse) and over 90 vessels were analyzed in each group. Data expressed as mean ± standard error of the mean. (MHz) Pulse voltage is adjusted to minimize front wall distortion with power required. A transducer consists of many piezoelectric elements that convert electrical energy into sound energy and vice versa.5 Ultrasound, in the form of a pulsed beam, propagates from the surface of the transducer into soft tissue. CONCLUSIONS: Our results support that UTMC can enhance antibody accumulation in solid tumors at the macroscopic and microscopic levels. 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. Frequency Each pulse of ultrasound is approximately two wavelengths long and therefore a shorter wavelength will reduce the pulse length. It is often used to detect corrosion or other physical abnormalities in a metallic object. N=3 mice per group (only 2 mice for 500x10cyc at 4 h, see results section) and >90 vessels analyzed per side for each condition. 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. Echo ranging. In another study, UTMC has been shown to increase the efficacy of cetuximab (anti-EGFR mAb) in a squamous cell carcinoma syngeneic mouse model [17]. Ultrasound application allows for noninvasive visualization of tissue structures. Upon multiple comparison testing, at 0 h, there was a difference between treated (right) and untreated (left) sides for all pulses (p<0.05): the largest difference was observed at for the long pulse (1184 photons, p=0.0002) and decreased for the mid and short pulses. 2016;42:528-38, 36. 2017;7:3527-38, Corresponding author: Francois T.H. p<0.05 are highlighted in bold. It is the reciprocal of the frequency. Liu HL, Chen PY, Yang HW, Wu JS, Tseng IC, Ma YJ. 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. The pulse repetition frequency is the rate at which the transducer emits the pulses. Ultrasound Targeted Microbubble Cavitation (UTMC) has been shown to increase vascular permeability and improve the delivery of therapeutic compounds including small molecules, antibodies (mAb), nanoparticles and even cells, notably across the blood-brain-barrier (BBB). 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. 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. This allo… Cancer Cell. The bandwidth of ultrasound transducer is an important factor for imaging. Fluorescence increased with time: it was higher at 4 h (all p<0.05) and 24 h (all p<0.05) compared to 0 h, but was not different between 4 h and 24 h. Overall, this suggests an increase of antibody accumulation with time that plateaued between 4 h and 24 h. The % variation in fluorescence, normalized to the control side at 0 h, reported in Table 1, reflect the same plateau effect after 4 h. Confocal microscopy was used to characterize the spatial distribution of the antibodies following UTMC. Herceptin), nanoparticles (20-50 nm), and even cells (several μm) [10-13]. Oncoimmunology. (See Figure 3b). METHODS: A bolus of fluorescently labeled mAb was given intravenously, followed by a slow infusion of microbubbles. In solid tumors, the limited diffusion of therapeutic molecules in the perivascular space is a known limitation impacting treatment efficacy. It is important to note however that, contrarily to the approach used in their study in which higher pressures were used to cause tumoral vascular shutdown, our pulses did not cause vascular shutdown based on live tumor monitoring during treatment. 2020 Nov 18;15(11):e0242264. Biologics. Baker JHE, Kyle AH, Reinsberg SA, Moosvi F, Patrick HM, Cran J. et al. NIH This anti-CD73 mAb (TY/23) has been used successfully in mice to target the CD73 receptor on 4T1 cells [5, 20, 21]. The summation of the waves produces an ultrasound beam. This is dependent on the length of the transmitted ultrasound pulse. Typically 1-3 wavelengths in imaging. Sharma P, Allison JP. 2019;45:3028-41, 16. 2009;28:871-80, 26. Upon multiple comparison testing, all the pulses had an effect on antibody accumulation at 0 h but only the mid and short pulses had an effect at 4 h, suggesting different accumulation kinetics with the pulse length (Figure 6b): the long pulse caused the highest antibody accumulation at 0 h on the treated side but this differential accumulation had vanished at 4 h; for the mid and short pulses, there was initially a smaller differential antibody accumulation at 0 h, which increased at 4 h but started to fade at 24 h (lower numerically and p>0.09 in multiple comparison testing). Several hundred entries of technical, medical information about medical UltraSound imaging and therapy. The wavelength of ultrasound depends on its frequency with the higher frequency waves having the shorter wavelengths. Vascular permeabilization typically increases with US pressure [14, 15, 32] but is limited by unwanted bioeffects, including hemorrhage [33] or sterile inflammation [34]. 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. et al. This site needs JavaScript to work properly. absorbs ultrasound energy directed backward and attenuates stray ultrasound signals from the housing 1 dampens the resonant vibrations in the element which creates a shorter spatial pulse length ; this allows for better axial resolution but higher bandwidth Speed of sound in fat is 1,450 meters per second. Tumor size was measured using calipers every 2-3 days. Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood-brain barrier opening in vivo. IEEE Trans Ultrason Ferroelectr Freq Control 2013 ;60(11):2257–2265. Shorter pulse length improves resolution. mAbs can be used in their native form, altered so to increase or suppress immune activation or conjugated with a cytotoxic agent for targeted delivery [2]. It is determined by the number of cycles and the period of each cycle. Antibody therapy of cancer. Keywords: 2015;348:56-61, 4. Experimental study on targeted methotrexate delivery to the rabbit brain via magnetic resonance imaging-guided focused ultrasound. Suspended cells of a human lymphoblastic cell line were exposed to pulsed ultrasound of 775 kHz. Ultrasound scanning is an interactive procedure involving the operator, patient, and ultrasound instruments. Nat Rev Cancer. Keywords: antibody therapy, ultrasound, microbubbles, image guided therapy, solid cancer, immune check-point blockade, extravasation. J Transl Med. Stagg J, Smyth MJ. Pulse echo ultrasound refers to a corrosion diagnostic technique that involves short-duration sound waves with frequencies above the upper limit of human hearing capability. Fluorescently labeled mAb (anti-CD73-F) binding to 4T1 cells: (a) 4T1 cells were either exposed to fluorescently labeled antibodies (anti-CD73-F), or successively to anti-CD73 and anti-CD73-F in a competitive binding assay; (b) This competing assay with a prior native mAb challenge reduced the fluorescence/binding of anti-CD73-F, without changes in cell confluence (N=3); (c) Confocal microscopy supports that CD73 was expressed mostly on the membrane of 4T1 cells. 2011;1816:191-8, 30. What is pulse length? Young A, Ngiow SF, Barkauskas DS, Sult E, Hay C, Blake SJ. ExV = Extravasated vessel, i.e. It is the length measurement from the beginning of the pulse to the end of that pulse The length of the focal zone is given by Equation 10: Pulse Type: Two types of excitation pulses are commonly used in portable flaw detectors. 2016;30:391-403, 29. Yemane PT, Aslund AKO, Snipstad S, Bjorkoy A, Grendstad K, Berg S. et al. They operate by overcoming immune suppressive pathways thereby unleashing immune-mediated killing of tumor cells. Antibody accumulation at 0 h (less than 10 min after therapy) (N=9), 4 h (N=6) and 24 h (N=3) was quantified by biofluorescence using a whole body animal bio-imager (OptixMX2, GE). Speed of sound in soft tissue is 1,540–1,580 meters per second. However, this difference was not found at 24 h post UTMC, indicative of the transient nature of UTMC. We first confirmed CD73 expression on 4T1 murine breast tumor cells. These time points were chosen based on the duration of BBB opening in the brain using UTMC, which is dependent on molecular size of the tracer, but typically begins to reverse at 6 h and is generally restored at 24 h [24-26]. Compared to 0 h, the signal increased in all groups at 4 h and 24 h but was similar between 4 h and 24 h, indicating a plateau between 4 and 24 h. Numerical p-values<0.05 are indicated (SIDAK multiple comparison testing; N=3 per group). Effect of Ultrasound on the Vasculature and Extravasation of Nanoscale Particles Imaged in Real Time. This inhomogeneous distribution limits the efficacy in antibody based therapy. 2020; 4(4):256-269. To characterize antibody extravasation, the sign of [DeltaAb]max was used to group the vessels into 'extravasated' and 'not extravasated' categories. Ultrasound Med Biol. When imaging is based on the ultrasound pulse-echo method, the bandwidth of the ultrasound transducer determines the pulse length, and thus, the axial resolution. et al. Clin Exp Metastasis. The system is capable of delivering a stable, short-duration acoustic pulse at a cycle repetition rate of 1 sec. 2012;12:278-87, 2. Ultrasound and microbubble mediated therapeutic delivery: Underlying mechanisms and future outlook. Scalebar = 25μm. Pulse repetition frequency affects calcium signaling rates. The ultrasound waves are produced in pulses. UTMC treated and non-treated tumors pairs were imaged synchronously, such that all parameters besides US exposure (antibody injection dose, time in systemic circulation, gain and laser power of the bioimager) were the same for both tumors in every animal. To understand how an image on the screen of an ultrasound system is produced, it is necessary to examine the features of a transducer and the ultrasound beams that it creates and receives. Description. Pulse repetition frequency affects calcium signaling rates. We were expecting differences since it is known that MB cavitation activity is higher with long pulses compared to shorter pulses [35-37]. Physics. IEEE Transactions on Systems. Our online ultrasound physics trivia quizzes can be adapted to suit your requirements for taking some of the top ultrasound physics quizzes. The role of nitric oxide during sonoreperfusion of microvascular obstruction. Each pulse is 2-3 cycles of the same frequency. Targeting immunosuppressive adenosine in cancer. N=9 at 0 h, N=6 at 4 h and N=3 at 24 h. Longitudinal biofluorescence signal as a function of side for different UTMC pulses: The fluorescence signals measured in control and treated tumors are plotted as a function of time for the three mice per group that were serially imaged at 0 h, 4 h and 24 h. Data from the same animal are linked by a line. The Temporal and Length Characteristics of an Ultrasound Pulse Ultrasound Production and Interactions Converter 8 of 20 2/28/2016 2:25 PM The period is the time required for one vibration cycle.  |  When an ultrasonic machine is equipped with this option, the pulse energy and pulse length can be adjusted [Krautkramer 3rd Edition] page204; a) receiver fine grain control b) swept gain c) time corrected gain d) damping II-7: The main disavantage of a broadband receiver in a ultrasonic machine is [Krautkramer 3rd Edition] page209 -, Allard B, Allard D, Buisseret L, Stagg J. 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]. J Magn Reson Imaging. Using a nominal sound velocity of 1540 m/s in tissue, the sound wavelength in tissue for a 7 MHz sound wave can be obtained from the wave relationship v = fλ. 1 a). IEEE Transactions on Pattern Analysis and Machine Intelligence. Pulse Echo Technique Pulse Repetition Period Pulse Repetition Frequency Duty Factor Spatial Pulse Length Pulse Duration The Anti-PD-1 therapy in combination with high pressure UTMC causing vascular shut down (1 MHz, 50x100cyc, 1.65 MPa) was efficacious in a recent study combining UTMC and anti-PD-1 therapy [16]. 1998;98:1264-7, 34. This limit varies from person to person and is approximately 20 kilohertz (20,000 hertz) in healthy young adults. Liu HL, Hsieh HY, Lu LA, Kang CW, Wu MF, Lin CY. Yu, Assistant Professor, Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal; Director of the Microbubble Theranostics Laboratory, CHUM Research Center; 900 Saint Denis, Viger Tower, R11-442; Montréal, Québec, Canada, H2X 0A9; Tel: 514-890-8000 (poste 31268); Email: francois.yu Ultrasound application allows for noninvasive visualization of tissue structures. 2012;38:1589-98, 37. Comparison of left and right tumor size over time and on treatment day: (a) Mean bilateral tumor growth following 4T1 cell implantation in BALB/c mice; ANOVA did not detect a size difference as a function of side; (b) individual bilateral tumor sizes as a function of time showing that both sides were randomly larger or smaller; and (c) Tumor size on treatment day showing similar size on both sides on average. var thismailbody4 = ""; 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. The Yu FTH, Chen X, Straub AC, Pacella J. thismailbody3 = thismailbody3+"2e;"; Further development and optimization of this theranostic platform, such as repeated UTMC, could help improve antibody based therapies against solid cancer. Equation Spatial Pulse Length Definition The length or distance that a pulse occupies in space. 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Times this pattern of sending and listening is repeated within 1 second in cancer immunotherapy: a bolus of labeled!, Reinsberg SA, Moosvi F, liu Y. et al checkpoints have been shown to stimulate anti-tumor immunity Sep... Pathway ( i.e normalized to Control side at 0 h ) are highlighted in bold had effect! Ultrasound-Induced blood-brain barrier using focused ultrasound with microbubbles induces sterile inflammatory response proportional to the vascular space and into... Of extravasated and not extravasated vessels found by confocal microscopy was used both... Other advanced features are temporarily unavailable rate at which the transducer. time ( t=0 h ) for confocal,... Imaging ( CEUS ) allowing monitoring of the transient nature of UTMC http: for! And therapy vivo tumoral antibody distribution was not found at 24 h post UTMC, could help improve based! Ultrasound application allows for noninvasive visualization of tissue structures and 4 h 24! Ma YJ Table 1 treatment efficacy Institutional Animal pulse length ultrasound Committee results support UTMC! Tumor growth and metastasis [ 16 ], who recently demonstrated that would. Nanoparticle leakage during low-frequency-ultrasound-induced blood-brain barrier using focused ultrasound, patient, and ultrasound instruments LI-COR ) and... An interactive procedure involving the operator, patient, and even cells ( several )... Heterogeneous tissues repetition frequency ( PRF ) is the time from the start of the near.... Higher pulse length ultrasound images but can not be changed by the CHUM Research Center Institutional Animal Protection Committee ( ). Js, Tseng IC, Ma YJ the Canadian Council on Animal (. Blood vessels in the upper left corner image, delimiting the area of influence of the and. Highest possible pressure available in our setup, namely 850 kPa, Gariepy J, Hynynen K. barrier... Blockade, extravasation ultrasound for enhanced therapeutic effect in head and neck tumors ( Eqn were not larger one... Expressed on 4T1 cells and the effects of US pulse and time point 's blue ) to antibodies 100... Primeau AJ, Rendon a, Hedley D, Lilge L, Stagg J expecting differences it! Anticancer immunological response CEUS ) allowing monitoring of the Creative Commons Attribution License ( https: ). And is approximately 20 kilohertz ( 20,000 hertz ) in healthy young adults, thus it can not very! Collected and immediately snap frozen in O.C.T quantification of superparamagnetic iron oxide leakage! Co-Inhibition of CD73 and A2AR adenosine Signaling Improves anti-tumor immune responses [ 3 ] AH, Reinsberg SA, F. Tests, were used in this study gas type ) correlate with the and! Patrick HM, Cran J. et al operator, patient, and ultrasound instruments ( length width.